tbuckley/cabot-search huggingface dataset:
Ability of multiparametric magnetic resonance imaging (MRI) to predict prostate tumor heterogeneity on targeted biopsy.
Authors: Samuel Gold, Jonathan Bloom, Graham R. Hale, Kareem Rayn, Sherif Mehralivand, Brad J. Wood, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2018)

113 Background: Prostate cancer (PCa) can show heterogeneous histology within lesions. MRI-targeted biopsy (Tbx) of the prostate improves PCa detection, but sampling within lesions has yet to be standardized. Furthermore, Tbx results are often heterogeneous as evidenced by differing histologic grades of Tbx cores within the same lesion. This introduces potential variability in biopsy results, on which clinical decisions are made. Here we aim to characterize lesion heterogeneity and identify predictive multiparametric MRI (mpMRI) features. Methods: A cohort of men who underwent mpMRI and Tbx between 2014-2017 were selected for analysis from a prospectively maintained database. To characterize lesion heterogeneity, only men with ≥2 positive Tbx cores were included. Histologic grades were scored according to International Society of Urological Pathology (ISUP) grades. Lesion heterogeneity, reported as a heterogeneity index (HI), was calculated as the difference of the average ISUP grades of Tbx cores per lesion from the maximum sampled ISUP grade of that lesion. Statistical analyses identified associations between imaging features and lesion heterogeneity. Results: 157 lesions in 114 patients met inclusion criteria. Maximum ISUP grade ranged from 1 to 5, with a median ISUP grade of 2. Higher ISUP grades were associated with greater lesion heterogeneity, HI for ISUP grade ≥3 = 0.58±0.11 vs &lt;3 = 0.29±0.08, p = 0.0001. In addition, increasing lesion size on mpMRI was associated with greater lesion heterogeneity, HI for ≥2cm = 0.52±0.14 vs &lt;2cm = 0.32±0.08, p = 0.0096. Finally, higher mpMRI suspicion scores were associated with increased heterogeneity vs lower suspicion scores, p = 0.048. Conclusions: mpMRI aids in characterizing PCa lesion heterogeneity to predict variability of histologic grades on Tbx. This information can assist Tbx planning to potentially reduce risks of upgrading on final pathology. Future research will examine how lesion heterogeneity can impact risk stratification and clinical decision-making for patients and practitioners. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program.
Research sponsors who fail to report results to be named and shamed
Authors: Anne Gulland
Journal: BMJ (2018)

Research organisations and drug companies who fail to report the results of clinical trials within 13 months of completion will be named on a new website.

The trial tracker, http://fdaaa.trialstracker.net, was launched by the campaign group All Trials after it got frustrated with the US Food and Drug Administration (FDA) for failing to sanction organisations which do not report the results of trials on ClinicalTrials.gov, as allowed under the FDA Amendment Act 2007.

The tracker was launched on 19 February and, using ClinicalTrials.gov’s data, it identifies trials as they reach 13 months from completion date and flags missing results. As the list grows, the website will …
OPTIMAL CUT-OFF VALUE OF NON-INVASIVE FRACTIONAL FLOW RESERVE FOR CORONARY REVASCULARIZATION USING A COMBINATION OF NUCLEAR CARDIOLOGY IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE
Authors: Koyuru Monno, Shunichi Yoda, Takumi Hatta, Takashi Mineki, Yasuyuki Suzuki, Naoya Matsumoto, Atsushi Hirayama
Journal: Journal of the American College of Cardiology (2018)
Cost-effectiveness of Magnetic Resonance Imaging in Cervical Clearance of Obtunded Blunt Trauma After a Normal Computed Tomographic Finding
Authors: Xiao Wu, Ajay Malhotra, Bertie Geng, Vivek B. Kalra, Khalid Abbed, Howard P. Forman, Pina Sanelli
Journal: JAMA Surgery (2018)

Magnetic resonance imaging (MRI) continues to be performed for cervical clearance of obtunded blunt trauma, despite poor evidence regarding its utility after a normal computed tomographic (CT) finding.To evaluate the utility and cost-effectiveness of MRI vs no follow-up after a normal cervical CT finding in patients with obtunded blunt trauma.This cost-effectiveness analysis evaluated an average patient aged 40 years with blunt trauma from an institutional practice. The analysis used a Markov decision model over a lifetime horizon from a societal perspective with variables from systematic reviews and meta-analyses and reimbursement rates from the Centers for Medicare & Medicaid Services, National Spinal Cord Injury Database, and other large published studies. Data were collected from the most recent literature available.No follow-up vs MRI follow-up after a normal cervical CT finding.In the base case of a 40-year-old patient, the cost of MRI follow-up was $14 185 with a health benefit of 24.02 quality-adjusted life-years (QALY); the cost of no follow-up was $1059 with a health benefit of 24.11 QALY, and thus no follow-up was the dominant strategy. Probabilistic sensitivity analysis showed no follow-up to be the better strategy in all 10 000 iterations. No follow-up was the better strategy when the negative predictive value of the initial CT was relatively high (>98%) or the risk of an injury treated with a cervical collar turning into a permanent neurologic deficit was higher than 25% or when the risk of a missed injury turning into a neurologic deficit was less than 58%. The sensitivity and specificity of MRI were varied simultaneously in a 2-way sensitivity analysis, and no follow-up remained the optimal strategy.Magnetic resonance imaging had a lower health benefit and a higher cost compared with no follow-up after a normal CT finding in patients with obtunded blunt trauma to the cervical spine, a finding that does not support the use of MRI in this group of patients. The conclusion is robust in sensitivity analyses varying key variables in the model. More literature on these key variables is needed before MRI can be considered to be beneficial in the evaluation of obtunded blunt trauma.
Model for Identifying Individuals at Risk for Esophageal Adenocarcinoma
Authors: Andrew T. Kunzmann, Aaron P. Thrift, Chris R. Cardwell, Jesper Lagergren, Shaohua Xie, Brian T. Johnston, Lesley A. Anderson, John Busby, Úna C. McMenamin, Andrew D. Spence, Helen G. Coleman
Journal: Clinical Gastroenterology and Hepatology (2018)
Welsh GPs reject 1.5% funding increase offer
Authors: Caroline White
Journal: BMJ (2012)

Doctors’ leaders in Wales have spurned the Welsh government’s 1.5% funding increase offer, made to entice general practitioners back to the negotiating table to hammer out an agreement on next year’s contract.

In a letter sent to GPs, David Bailey, chair of the BMA’s General Practitioners Committee (Wales), said that the Welsh government wanted “to impose very significant changes to practice contracts.”

And he made it clear that BMA Wales “has no intention of legitimising something so fundamentally damaging to the profession by returning to the table.”

Bailey said that GPs had been presented with a “challenging mandate,” but had worked hard to come up with a …
A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population.
Authors: Fatima Karzai, Ravi Amrit Madan, Helen Owens, Anna Couvillon, Amy Hankin, Monique Williams, Marijo Bilusic, Lisa M. Cordes, Jane B Trepel, Keith Killian, Paul S. Meltzer, James L. Gulley, Jung-min Lee, William L. Dahut
Journal: Journal of Clinical Oncology (2018)

163 Background: Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi). Immune checkpoint blockade may increase the proportion of patients that respond to PARPi. We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC (NCT02484404). Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and disease that is amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Core biopsies undergo mutational analysis. Results: In the first 17 pts, median age is 66 (range 45-79 years), median baseline PSA is 79.67 ng/mL [3.93-2356 ng/mL]). Median Gleason score is 8. 6 patients have bone only disease and 11 patients have bone and soft tissue/visceral disease. Median number of cycles is 7 (2-17). Grade 3/4 adverse events include anemia 4/17 (24%), lymphopenia 2/17 (12%), infection 2/17 (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps [1/17 each, (6%)]. 8/17 pts (47%) had PSA responses &gt;50%. 6 of these pts had mutations in the DNA damage repair pathways (DNAdr). 2/17 pts (11%) had PSA responses &gt;30% with no known mutations in DNAdr. 4 pts had a PR. The 12 month PFS is 51.5% (95% CI: 25.7-72.3%). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404.
ENDOTHELIN-1 PREDICTS INCIDENT HEART FAILURE, INCIDENT MYOCARDIAL INFARCTION, CARDIOVASCULAR MORTALITY, AND ALL-CAUSE MORTALITY IN PATIENTS UNDERGOING DIAGNOSTIC CORONARY ANGIOGRAPHY: RESULTS FROM THE CATHETER SAMPLED BLOOD ARCHIVE IN CARDIOVASCULAR DISEASES (CASABLANCA) STUDY
Authors: Nasrien E. Ibrahim, Shreya Shrestha, Cian McCarthy, Asya Lyass, Yiwei Li, Hanna Gaggin, Roland R.J. van Kimmenade, Joseph Massaro, Ralph D’Agostino, James Januzzi
Journal: Journal of the American College of Cardiology (2018)
Establishing a Vision and Eye Health Surveillance System for the Nation: A Status Update on the Vision and Eye Health Surveillance System
Authors: David B. Rein, John S. Wittenborn, Emily A. Phillips, Jinan B. Saaddine, Farah Ahmed, Mike Ammerman, Mary Frances Cotch, Clare Davidson, Michelle Doherty, Erkan Erdem, Abraham D. Flaxman, David S. Friedman, Kevin M. Jackson, Charlotte E. Joslin, Barbara E.K. Klein, Ronald Klein, Tracey P. Koehlmoos, Phoebe Lamuda, Paul P. Lee, Yao Liu, Flora Lum, Eve D. Mokotoff, Nnenna L. Okeke, Emily A. Phillips, Nita P. Sinha, Bonnielin K. Swenor, Jeff Todd
Journal: Ophthalmology (2018)
The Science of Obesity Management: An Endocrine Society Scientific Statement
Authors: George A Bray, William E Heisel, Ashkan Afshin, Michael D Jensen, William H Dietz, Michael Long, Robert F Kushner, Stephen R Daniels, Thomas A Wadden, Adam G Tsai, Frank B Hu, John M Jakicic, Donna H Ryan, Bruce M Wolfe, Thomas H Inge
Journal: Endocrine Reviews (2018)

The prevalence of obesity, measured by body mass index, has risen to unacceptable levels in both men and women in the United States and worldwide with resultant hazardous health implications. Genetic, environmental, and behavioral factors influence the development of obesity, and both the general public and health professionals stigmatize those who suffer from the disease. Obesity is associated with and contributes to a shortened life span, type 2 diabetes mellitus, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner—the more weight lost, the better the outcome. The phenotype of "medically healthy obesity" appears to be a transient state that progresses over time to an unhealthy phenotype, especially in children and adolescents. Weight loss is best achieved by reducing energy intake and increasing energy expenditure. Programs that are effective for weight loss include peer-reviewed and approved lifestyle modification programs, diets, commercial weight-loss programs, exercise programs, medications, and surgery. Over-the-counter herbal preparations that some patients use to treat obesity have limited, if any, data documenting their efficacy or safety, and there are few regulatory requirements. Weight regain is expected in all patients, especially when treatment is discontinued. When making treatment decisions, clinicians should consider body fat distribution and individual health risks in addition to body mass index.
DESCRIPTION OF IMAGING PARAMETERS TO ASSESS FEMOROPOPLITEAL ARTERY STENT EXPANSION WITH INTRAVASCULAR ULTRASOUND
Authors: Bo Sun, Amutharani Baskar, Haekyung Jeon-Slaughter, Hao Xu, Hua Lu, Shirling Tsai, Bala Ramanan, Houman Khalili, Emmanouil S. Brilakis, Subhash Banerjee
Journal: Journal of the American College of Cardiology (2018)
Pembrolizumab for recurrent or advanced prostate cancer.
Authors: Juliana Higa, Kirk Wilenius, Joanne B. Weidhaas, Claire Larsen, Richard Y. Lam, Jeffrey Turner, Mark C. Scholz
Journal: Journal of Clinical Oncology (2018)

250 Background: Two previous Phase II trials studying pembrolizumab (Pembro) in 38 patients suggest it may be efficacious for prostate cancer (PC). Methods: Fifty-four consecutive men with recurrent or advanced prostate cancer were treated with 1 to 9 cycles of Pembro 200 mg every 3 weeks with or without SBRT at a private medical oncology clinic specializing in PC. Charts were retrospectively reviewed for response and toxicity. Definitions: Response (R) = &gt;50% PSA decline; Progressive Disease (PD) = &gt;50 % PSA increase. Stable Disease (SD)= neither response or progression. Results: 43 men completed 3 cycles of Pembro and were evaluable for toxicity. Toxicity was comparable to reports with other cancers besides PC, with 30.2% (13/43) having Grade 2 or higher toxicity. 31 men completed 4 cycles of Pembro and were evaluable for response. For the 31, the median Gleason score was 4+4=8. Treatment prior to Pembro was enzalutamide (26), abiraterone (18), and sipuleucel-t (23) and docetaxel (20). All but 4 men were castrate resistant (CRPC). Ten men got SBRT to a metastasis shortly before or during Pembro. Number of mutations were determined by the Guardant 360 assay. 17/31 (55%) were responders (19%) or had stable disease (35%). Characteristics of the two subgroups, R (6/31) + SD (11/31) versus PD (14/31), are presented in the table. Conclusions: Disease stabilization or response occurred in slightly more than half of the men treated with 4 or more cycles of Pembro. These positive responses were more common in men with lower PSA, fewer bone mets, fewer mutations, less previous chemotherapy, and there was a trend toward greater benefit in castrate sensitive disease and older men. In a separate abstract related to this patient cohort, the predictive ability of inherited mutations disrupting microRNA signaling were assessed for their capacity to predict toxicity (n=40). The table shows medians of the subgroups in the left 5 columns and the total number of patients in the right 3 columns for the 31 patients evaluable for response. [Table: see text]
I am currently being paid at year 6 on an SHO salary scale for an NHS clinical fellow (research) post in neurology. Will my salary drop to year 1 registrar when I take up a numbered SpR post?
Authors: Trevor Pickersgill
Journal: BMJ (2005)

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 (www.bmjcareers.com/advicezone) 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.
An open label phase 1b/2 trial of TRC105 and sorafenib in patient with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064).
Authors: Kanwal Pratap Singh Raghav, Kabir Mody, Tim F. Greten, Ravi Kumar Paluri, Richard T. Lee, Brian E Simpson, Bonne J. Adams, Charles P. Theuer, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2018)

301 Background: Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody potentiates anti-tumor activity of sorafenib (S) in preclinical HCC models. The combination of TRC105 and S demonstrated encouraging evidence of activity, including a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, fatigue, headache and anemia. Methods: Following dose escalation, 21 pts will be enrolled at the RP2D. Four objective responses are required to reject the null hypothesis that the true response rate probability is &lt; 5% with an alpha level of 0.1 and 80% power. Secondary endpoints: DR, PFS, frequency and severity of AEs, PK, immunogenicity, angiogenic biomarkers. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Four pts have been enrolled in phase 1b at TRC105 10 mg/kg (n=4) weekly for four doses and 15 mg/kg every other week thereafter + S 800 mg daily without DLT. One of 3 evaluable pts achieved PR (41% reduction), ongoing at month 4. Serum levels of TRC105 exceeded the target concentration following 4 weekly doses of TRC105 at 10 mg/kg (mean = 59 µg/ml, range 43-80). Mean trough concentration decreased following every other week dosing (mean = 21 µg/ml, range 17-31). Common TRC105 related AEs included ≤ G2 epistaxis and G1 headache. Common S related AEs included G3 hand foot syndrome, ≤G3 periodontal disease, G2 hypertension, ≤G2 increased lipase, ≤G2 fatigue and G1 epistaxis. Conclusions: TRC105 dosed by a hybrid schedule of 10 mg/kg weekly for four doses followed by every other week dosing at 15 mg/kg was tolerable and did not potentiate the toxicity of S. The combination of TRC105 + S demonstrated additional signs of activity, including a PR in 1/3 evaluable pts. 21 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.
ANTICOAGULATION THERAPY FOLLOWING ACUTE AORTIC DISSECTION
Authors: Jean Bismuth, Muhammad Zubair, Udo Sechtem, Kevin Harris, Toru Suzuki, Ali Khoynezhad, Linda Pape, Emil Missov, Anil Bhan, Alan Braverman, Santi Trimarchi, Christoph Nienaber, Daniel Montgomery, Kim Eagle, Anthony L. Estrera, Eric Isselbacher, Arturo Evangelista
Journal: Journal of the American College of Cardiology (2018)
Integrating HIV and hypertension management in low-resource settings: Lessons from Malawi
Authors: Pragna Patel, Colin Speight, Alice Maida, Fleetwood Loustalot, Denise Giles, Sam Phiri, Sundeep Gupta, Pratima Raghunathan
Journal: PLoS Medicine (2018)

Hypertension is the leading risk factor for cardiovascular disease, the most common cause of death worldwide.• In 2011, the United Nations declared that lessons learned from national human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), tuberculosis, and malaria programs in low-and middle-income countries should be harnessed for effective integration of communicable and noncommunicable disease initiatives.• HIV clinical service delivery facilities offer a platform on which to enhance care by offering noncommunicable disease interventions.• Given Malawi's high prevalence of hypertension, with an estimated one-third of adults in the country affected, we sought to incorporate hypertension management in HIV care delivery sites using standardized treatment protocols and patient registries to monitor treatment outcomes.• The overall aim was to create a reproducible and scalable hypertension management model for HIV-infected persons that is cost effective and that can be used to inform national scale-up of hypertension and other chronic disease care models.• We describe pertinent issues that were raised during the design and implementation of the program, particularly important for the enhanced care of HIV-infected persons.
India’s antibiotic combinations thwart efforts to curb drug resistance, say researchers
Authors: Frederik Joelving
Journal: BMJ (2018)

Rising sales of antibiotic combinations in India could be undermining global efforts to limit antimicrobial resistance, says a study that found dozens of unapproved and sometimes risky formulations on the market.1

India is the world’s top consumer of antibiotics and a hotbed for drug evading bacteria,23 which are exported globally by travellers. The problem is compounded by widespread use of drug combinations that mix antimicrobials and other medicines—known as fixed dose combinations (FDCs)—because one or more of the ingredients is usually unnecessary. This fuels overuse and thus resistance, needlessly exposing patients to side effects.

“We can’t blame all antimicrobial resistance on India, but they are creating a problem for themselves and everybody else with these fixed dose combinations,” said Kathleen Holloway, a retired World Health Organization staffer based at the University of Sussex, UK, who has studied drug resistance in Asia but was not involved in the new study. “There is absolutely no excuse for having all these things on the market.”

Combination products account for almost half of the drugs on sale in India. …
Learning, activity… and injury? Caring for young athletes through appropriately designed modified (developmental) sport
Authors: Machar Reid, Tim Buszard, Damian Farrow
Journal: British Journal of Sports Medicine (2018)

We enjoyed 2017’s American Medical Society for Sports Medicine issue of the BJSM focused on ‘Key issues in the care of young athletes’ that included insightful articles on sports specialisation1 and cardiovascular pre-participation screening.2 However, we would like to see a future issue address modified sport programmes which occupy playing fields on weekends and feature prominently in marketing campaigns of almost every sport interested in competing for the hearts and minds of children. Modified sport matters. It matters because it generally represents a child’s entry into sport and, if effective, helps to retain them in sport.3 

Modified sport presents sports administration, medicine and science professionals with opportunities to ensure that the early sports experience of children is delivered in conditions that are suitable for their age or stage of development. In this way, modified sport recognises that the needs and abilities of children are different to adults and attempts to adapt its equipment and rules accordingly. Most sports now provide age-based guidelines on …