tbuckley/cabot-search huggingface dataset:
TAK1ng control: TAK1 restrains NLRP3 activation
Authors: Matthew Stephen Mangan, Eicke Latz
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, Malireddi et al. (https://doi.org/10.1084/jem.20171922) demonstrate that macrophage-specific loss of TAK1 causes spontaneous NLRP3 inflammasome activation, driven by unregulated TNF secretion and signaling. This has implications for therapeutically targeting TAK1, enhancing its potential function as an anticancer drug treatment.
Guidance is published on dealing with concerns about a doctor’s behaviour
Authors: Helen Jaques
Journal: BMJ (2012)

The National Clinical Assessment Service (NCAS) has published new best practice guidance to help NHS organisations deal effectively with concerns about a doctor’s behaviour.

NCAS advises healthcare managers and NHS organisations on how to deal locally with concerns about the performance of doctors, dentists, and pharmacists. More than half (57%) of the 3000 cases referred to it between December 2007 and October 2010 had some type of behaviour or conduct …
Abstract P2-12-08: Rates of re-excision surgery after implementation of consensus guidelines on margins for breast- conserving surgery in stage I and II invasive breast cancer: A Nova Scotian experience
Authors: AE Drohan, LK Helyer
Journal: Cancer Research (2018)

Abstract Background: In Canada, most women with early invasive breast cancer will be treated with breast-conserving surgery (BCS). The proportion of patients requiring re-excision surgery after BCS varies province to province. Until recently, there was no universally accepted definition for adequate margin width following BCS. The Society of Surgical Oncology (SSO) and American Society for Radiation Oncology (ASTRO) published consensus guidelines in 2014 to help regulate practice. The objective of this study was to determine the proportion of patients undergoing re-excision surgery before and after guideline implementation at our institution. Methods: We performed a retrospective review of all patients with invasive breast cancer and/or ductal carcinoma in situ (DCIS) who underwent re-excision surgery between October 1, 2010- October 31, 2011 (pre-guideline) and October 1, 2014- May 30, 2016 (post-guideline). The proportion of patients requiring re-excision surgery was calculated for each time period and patient characteristics and clinical outcomes were compared. Results: There were 188 patients identified who underwent BCS in the pre-guideline time period and 411 patients in the post-guideline time period. The proportion of patients undergoing re-excision surgery significantly decreased from 13.8 % to 7.8 % after guideline implementation (p = 0.02). Patient characteristics were similar between those who underwent re-excision before and after guideline implementation. In patients requiring re-excision surgery, histological and pathological features were similar between time periods. Margin width and indication for re-excision surgery varied between time periods. Among women who had re-excision surgery in the pre-guideline group, most (50%) had an invasive cancer margin &amp;gt; 1 mm. However, after guideline implementation, a frankly positive invasive cancer margin was the most common indication for re-excision surgery (65%). No significant differences in clinical outcomes were observed between patients who underwent re-excision surgery before and after guideline implementation. Conclusion: The proportion of patients undergoing re-excision surgery after BCS has significantly decreased after SSO-ASTRO guideline implementation at our institution. This data suggests that among women with invasive breast cancer and/or DCIS, the implementation of SSO-ASTRO guidelines has led to a 43.5% decline in re-excision surgery. Citation Format: Drohan AE, Helyer LK. Rates of re-excision surgery after implementation of consensus guidelines on margins for breast- conserving surgery in stage I and II invasive breast cancer: A Nova Scotian experience [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-08.
Size-focality-invasion in upper tract urothelial carcinoma (SFI-UTUC): A novel imaging-based score to predict survival outcomes.
Authors: Zachary Hamilton, Miki Haifler, Laura-Maria Krabbe, Stephen Ryan, Madhumitha Reddy, Sean Berquist, Timothy N Clinton, Aaron Bloch, Charles Field, Sunil Patel, Brittney Cotta, Vitaly Margulis, Robert Uzzo, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2018)

475 Background: Upper tract urothelial cell carcinoma (UTUC) is an uncommon malignancy with disparate outcomes. We developed a novel morphometric scoring system for prediction of oncologic and survival outcomes before nephroureterectomy (NU). Methods: Retrospective, multicenter analysis of UTUC patients who underwent NU after negative metastatic workup. Preoperative CT-urography was used to evaluate scores, based on 3 factors (Tumor Size, Focality, Invasion of architecture) with a score of 1-3 based on degree of each factor (total score 3-9). Primary outcome was overall survival (OS). Secondary outcomes were recurrence and recurrence free survival (RFS). Multivariable (MVA) and Kaplan-Meier (KMA) analyses were utilized. Results: We analyzed 244 patients (mean age 70.9, mean follow up 29.5 months). 61% with SFI-UTUC score 3-6 and 39% were score 7-9. No difference in age, gender, comorbid conditions, surgical approach, or complications between groups. Score 7-9 had a higher rate of pN+ disease (24.2% vs. 8.1%, p=0.002) but similar nuclear grade. All-cause mortality was higher for score 7-9 (47.4% vs. 28.9%, p=0.004). On MVA for all-cause mortality, age (OR 1.1), recurrence (OR 4.4) and score 7-9 (OR 2.0) were significant (p&lt;0.05). KMA for OS demonstrated 5 year OS of 57.0% for score 3-6 and 34.1% for score 7-9 (p&lt;0.01). KMA for RFS was significant for renal UTUC location with 5 year RFS of 72.3% for score 3-6 and 54.2% for score 7-9, (p&lt;0.01). Conclusions: A novel scoring system for UTUC preoperative imaging may predict OS for tumors in renal and ureteral locations, as well as RFS for renal locations. Renal location. [Table: see text]
Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005–2014)
Authors: Patricia P. Chang, Lisa M. Wruck, Eyal Shahar, Joseph S. Rossi, Laura R. Loehr, Stuart D. Russell, Sunil K. Agarwal, Suma H. Konety, Carlos J. Rodriguez, Wayne D. Rosamond
Journal: Circulation (2018)

Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex.The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (≥55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746).Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ≈10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%).Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men.
Simulation study of volumetric modulated arc therapy for thoracic esophageal cancer using automated-radiotherapy planning software.
Authors: Yuji Murakami, Yasushi Nagata, Tomoki Kimura, Ikuno Nishibuchi, Takeo Nakashima
Journal: Journal of Clinical Oncology (2018)

158 Background: To prevent cardiac toxicity after chemoradiotherapy for esophageal cancer (EC), decrease of high irradiation dose to the heart without expanding the volume of lung irradiated low dose is needed, but this is not easy under the conventional techniques. Purpose of this study is to investigate the utility of volumetric modulated arc therapy using automated-radiotherapy planning software (auto-VMAT) to solve this issue. Methods: In this simulation study, data of 12 patients with stage I-III ECs previously treated by 3D-conformal radiotherapy (3DCRT) was used. We performed auto-VMAT planning using commercially available ‘Pinnacle3 Auto-Planning’ software. Targets for gross tumor (PTV1) and elective nodal region (PTV2), and organs at risk (OARs: lung, heart, left ventricle, epicardium, left pleura, liver and spinal cord) were delineated. Multi-portal beams were used for 3DCRT and dose description was 40 Gy in 20 fractions for PTV1+2 and 20 Gy in 10 fractions-boost for PTV1. We used the simultaneous integrated boost method for auto-VMAT with a dose description of 60 Gy for PTV1 and 48 Gy for PTV2 in 30 fractions. We performed planning in consideration with decrease of volumes irradiated middle to high dose in left ventricle and achievement of volume irradiated 5 Gy (V5) in lung &lt; 50% as high-priority dose constraints. Results: Prescribed dose coverage of PTVs was equivalent between 3DCRT and auto-VMAT, while auto-VMAT showed better dose-conformity. Auto-VMAT showed a significant decrease of mean dose and V20-V60 in heart, left ventricle and epicardium and significant decrease of V50-V60 in lung and left pleura. V5 in lung was equivalent between 3DCRT and auto-VMAT (46.6±9.6% vs 45.6±4.7%; p = 0.72). Auto-VMAT achieved the V5 in lung &lt; 50% in 10 among 12 patients and the max V5 in lung was 52.5%. Conclusions: Auto-VMAT for ECs achieved better dose conformity of targets, decrease of middle-high dose in heart, left ventricle and epicardium, and equivalent low dose volumes in lung. Auto-VMAT planning brings high quality dose distribution, uniformity of quality of planning, laborsaving and timesaving in treatment planning.
HEART FAILURE AS AN ENTRY POINT FOR SEVERE CARDIOVASCULAR DISEASE IN SUB-SAHARAN AFRICA: 10-YEAR EXPERIENCE WITH NURSE-LED DIAGNOSIS AND TREATMENT AT DISTRICT HOSPITALS IN RURAL RWANDA
Authors: Lauren Eberly, Emmanuel Rusingiza, Paul Park, Gedeon Ngoga, Symaque Dusabeyezu, Francis Mutabazi, Emmanuel Harerimana, Joseph Mucumbitsi, Philippe F. Nyembo, Ryan Borg, Cyprien Gahamanyi, Cadet Mutumbira, Evariste Ntaganda, Gene F. Kwan, Gene Bukhman
Journal: Journal of the American College of Cardiology (2018)
Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy
Authors: Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A. Kucaba, Katherine A. Murphy, Britnie R. James, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam
Journal: Biomaterials (2018)
THIRTY DAY READMISSIONS AND PACEMAKER IMPLANTATION RATES FOR SYNCOPE INSIGHTS FROM UNITED STATES NATIONWIDE READMISSION DATABASE
Authors: Venkat Lakshmi Kishan Vuddanda, Naga Sai Shravan Turaga, Zubair Shah, Srikanth Yandrapalli, Mohammad-Ali Jazayeri, Mohit Turagam, Seth Sheldon, Dhanunjaya R. Lakkireddy, Moussa Mansour, Edwin Heist
Journal: Journal of the American College of Cardiology (2018)
Bioinspired Multifunctional Melanin-Based Nanoliposome for Photoacoustic/Magnetic Resonance Imaging-Guided Efficient Photothermal Ablation of Cancer
Authors: Liang Zhang, Danli Sheng, Dong Wang, Yuanzhi Yao, Ke Yang, Zhigang Wang, Liming Deng, Yu Chen
Journal: Theranostics (2018)

Background: The construction of theranostic nanosystems with concurrently high biosafety and therapeutic performance is a challenge but has great significance for the clinical translation of nanomedicine for combating cancer. Methods: Bio-inspired melanin-based nanoliposomes (Lip-Mel) as theranostic agents were constructed for simultaneous photoacoustic (PA) imaging- and T1-weighted magnetic resonance (MR) imaging-guided photothermal ablation of tumors, which was demonstrated both in vitro and in vivo. The high biosafety of Lip-Mel was also systematically evaluated. Results: The achieved Lip-Mel nanoliposomes demonstrated their imaging capability for both PA and T1-weighted MR imaging (r1 = 0.25 mM-1·s-1) both in vitro and in vivo, providing the potential for therapeutic guidance and monitoring. Importantly, the desirable photothermal-conversion efficiency of the as-prepared Lip-Mel achieved complete eradication of tumors in breast cancer-bearing mice, exhibiting remarkable photothermal-based therapeutic performance. In particular, the efficient encapsulation of melanin into the PEGylated liposome mitigated the potential toxicity of melanin and improved the photothermal performance of the loaded melanin. Systematic in vivo biosafety evaluations demonstrated the high biocompatibility of Lip-Mel at a high dose of 100 mg/kg. Conclusion: In this work, we reported a bioinspired strategy where melanin, a natural product in the human body, is encapsulated into PEGylated nanoliposomes for efficient theranostics with high biocompatibility. This work provides a new strategy for creating desirable theranostic agents with concurrent high biocompatibility and satisfactory theranostic performance through the use of materials that totally originate from biosystems.
Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets
Authors: Claire E. Macdougall, Elizabeth G. Wood, Jakob Loschko, Valeria Scagliotti, Féaron C. Cassidy, Mark E. Robinson, Niklas Feldhahn, Leandro Castellano, Mathieu-Benoit Voisin, Federica Marelli-Berg, Carles Gaston-Massuet, Marika Charalambous, M. Paula Longhi
Journal: Cell Metabolism (2018)
What are the chances of getting a dermatology training post if I have also got an MSc in dermatology in Wales?
Authors: Susannah Baron
Journal: BMJ (2007)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site <b>www.bmjcareers.com/advicezone</b>
Clinical use of lentiviral vectors
Authors: Michael C. Milone, Una O’Doherty
Journal: Leukemia (2018)

Viral vectors provide an efficient means for modification of eukaryotic cells, and their use is now commonplace in academic laboratories and industry for both research and clinical gene therapy applications. Lentiviral vectors, derived from the human immunodeficiency virus, have been extensively investigated and optimized over the past two decades. Third-generation, self-inactivating lentiviral vectors have recently been used in multiple clinical trials to introduce genes into hematopoietic stem cells to correct primary immunodeficiencies and hemoglobinopathies. These vectors have also been used to introduce genes into mature T cells to generate immunity to cancer through the delivery of chimeric antigen receptors (CARs) or cloned T-cell receptors. CAR T-cell therapies engineered using lentiviral vectors have demonstrated noteworthy clinical success in patients with B-cell malignancies leading to regulatory approval of the first genetically engineered cellular therapy using lentiviral vectors. In this review, we discuss several aspects of lentiviral vectors that will be of interest to clinicians, including an overview of lentiviral vector development, the current uses of viral vectors as therapy for primary immunodeficiencies and cancers, large-scale manufacturing of lentiviral vectors, and long-term follow-up of patients treated with gene therapy products.
IMPACT OF THE CMS ALGORITHM FOR DOOR-TO-BALLOON TIME PUBLIC REPORTING ON DOOR-TO-BALLOON TIME PERFORMANCE
Authors: Chetan Huded, Kathleen Kravitz, Venu Menon, Travis Gullett, Scott Hantz, Stephen Ellis, Damon Kralovic, Seth Podolsky, Stephen Meldon, Deborah Brosovich, Elizabeth Smith, Samir Kapadia, Umesh Khot
Journal: Journal of the American College of Cardiology (2018)
Affordability and availability of off-patent drugs in the United States—the case for importing from abroad: observational study
Authors: Ravi Gupta, Thomas J Bollyky, Matthew Cohen, Joseph S Ross, Aaron S Kesselheim
Journal: BMJ (2018)

To evaluate whether off-patent prescription drugs at risk of sudden price increases or shortages in the United States are available from independent manufacturers approved in other well regulated settings around the world.Observational study.Off-patent drugs in the USA and approved by the Food and Drug Administration, up to 10 April 2017.Novel tablet or capsule prescription drugs approved by the FDA since 1939 that were no longer protected by patents or other market exclusivity and had up to three generic versions.Number of additional manufacturers that had obtained approval from any of seven non-US regulators with similar standards (European Medicines Agency (European Union), HealthCanada (Canada), Therapeutic Goods Association (Australia), Medsafe (New Zealand), Swissmedic (Switzerland), Medicines Control Council (South Africa), and the Israel Health Ministry). Association with drug characteristics including US orphan drug designation for drugs treating rare diseases, World Health Organization essential medicine designation, treatment area, drug product complexity (that is, with attributes that could complicate establishing bioequivalence or manufacturing), and total Medicaid spending in 2015.Of 170 eligible study drugs, more than half (109, 64%) had at least one manufacturer approved by a non-US regulator and 32 (19%) had four or more. Among 44 (26%) drugs with no FDA approved generic versions, 21 (48%) were available from at least one manufacturer approved by one of the seven non-US regulators, and two (5%) by four or more manufacturers. Across all drugs and regulators (including the FDA), 66 (39%) drugs were available from four or more total manufacturers. Of 109 drugs with at least one non-US regulator approved manufacturer, 12 (11%) were approved for patients with rare diseases and 29 (27%) were WHO designated essential medicines; only 12 (11%) were complex products that might be more complicated to import. The highest numbers of drugs were indicated for treating cardiovascular diseases, diabetes, or hyperlipidemia (19, 17%); psychiatric disease (16, 15%); and infectious diseases (15, 14%). In 2015, Medicaid alone spent nearly US$700m (£508m; €570m) on generic drugs without adequate US competition that could have had a manufacturer approved by non-US peer regulatory agencies.In this study, more than half the off-patent drugs with no generic competition in the USA had at least one independent manufacturer approved by a non-US peer regulatory agency; slightly fewer than half had four or more total manufacturers. Facilitating US patient access to such manufacturers could help sustain affordable access to essential off-patent drugs.
Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis
Authors: Alessandro Mantovani, Christopher D. Byrne, Enzo Bonora, Giovanni Targher
Journal: Diabetes Care (2018)

OBJECTIVE Several studies have explored the impact of nonalcoholic fatty liver disease (NAFLD) on risk of incident type 2 diabetes. However, the extent to which NAFLD may confer risk of incident diabetes remains uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes. RESEARCH DESIGN AND METHODS We collected data using PubMed, Scopus, and Web of Science from January 2000 to July 2017. We included only large (n ≥500) observational studies with a follow-up duration of at least 1 year in which NAFLD was diagnosed on imaging methods. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling. RESULTS A total of 19 observational studies with 296,439 individuals (30.1% with NAFLD) and nearly 16,000 cases of incident diabetes over a median of 5 years were included in the final analysis. Patients with NAFLD had a greater risk of incident diabetes than those without NAFLD (random-effects hazard ratio [HR] 2.22, 95% CI 1.84–2.60; I2 = 79.2%). Patients with more “severe” NAFLD were also more likely to develop incident diabetes; this risk increased across the ultrasonographic scores of steatosis (n = 3 studies), but it appeared to be even greater among NAFLD patients with advanced high NAFLD fibrosis score (n = 1 study; random-effects HR 4.74, 95% CI 3.54–5.94). Sensitivity analyses did not alter these findings. Funnel plot and Egger test did not reveal significant publication bias. Study limitations included high heterogeneity, varying degrees of confounder adjustment across individual studies, and lack of studies using liver biopsy. CONCLUSIONS NAFLD is significantly associated with a twofold increased risk of incident diabetes. However, the observational design of the eligible studies does not allow for proving causality.
Impaired Recognition of Positive Emotions in Individuals with Posttraumatic Stress Disorder, Cumulative Traumatic Exposure, and Dissociation
Authors: Sandra Passardi, Peter Peyk, Michael Rufer, Michael M. Plichta, Christoph Mueller-Pfeiffer, Tanja S.H. Wingenbach, Katayun Hassanpour, Ulrich Schnyder, Monique C. Pfaltz
Journal: Psychotherapy and Psychosomatics (2018)
Key design considerations for adaptive clinical trials: a primer for clinicians
Authors: Kristian Thorlund, Jonas Haggstrom, Jay JH Park, Edward J Mills
Journal: BMJ (2018)

This article reviews important considerations for researchers who are designing adaptive clinical trials. These differ from conventional clinical trials because they allow and even enforce continual modifications to key components of trial design while data are being collected. This innovative approach has the potential to reduce resource use, decrease time to trial completion, limit allocation of participants to inferior interventions, and improve the likelihood that trial results will be scientifically or clinically relevant. Adaptive designs have mostly been used in trials evaluating drugs, but their use is spreading. The US Food and Drug Administration recently issued guidance on adaptive trial designs, which highlighted general principles and different types of adaptive clinical trials but did not provide concrete guidance about important considerations in designing such trials. Decisions to adapt a trial are not arbitrary; they are based on decision rules that have been rigorously examined via statistical simulations before the first trial participant is enrolled. The authors review important characteristics of adaptive trials and common types of study modifications and provide a practical guide, illustrated with a case study, to aid investigators who are planning an adaptive clinical trial