tbuckley/cabot-search huggingface dataset:
The Association of Long-Term Exposure to Particulate Matter Air Pollution with Brain MRI Findings: The ARIC Study
Authors: Melinda C. Power, Archana P. Lamichhane, Duanping Liao, Xiaohui Xu, Clifford R. Jack, Rebecca F. Gottesman, Thomas Mosley, James D. Stewart, Jeff D. Yanosky, Eric A. Whitsel
Journal: Environmental Health Perspectives (2018)

Background: Increasing evidence links higher particulate matter (PM) air pollution exposure to late-life cognitive impairment. However, few studies have considered associations between direct estimates of long-term past exposures and brain MRI findings indicative of neurodegeneration or cerebrovascular disease. Objective: Our objective was to quantify the association between brain MRI findings and PM exposures approximately 5 to 20 y prior to MRI in the Atherosclerosis Risk in Communities (ARIC) study. Methods: ARIC is based in four U.S. sites: Washington County, Maryland; Minneapolis suburbs, Minnesota; Forsyth County, North Carolina; and Jackson, Mississippi. A subset of ARIC participants underwent 3T brain MRI in 2011–2013 (n=1,753). We estimated mean exposures to PM with an aerodynamic diameter less than 10 or 2.5μm (PM10 and PM2.5) in 1990–1998, 1999–2007, and 1990–2007 at the residential addresses of eligible participants with MRI data. We estimated site-specific associations between PM and brain MRI findings and used random-effect, inverse variance–weighted meta-analysis to combine them. Results: In pooled analyses, higher mean PM2.5 and PM10 exposure in all time periods were associated with smaller deep-gray brain volumes, but not other MRI markers. Higher PM2.5 exposures were consistently associated with smaller total and regional brain volumes in Minnesota, but not elsewhere. Conclusions: Long-term past PM exposure in was not associated with markers of cerebrovascular disease. Higher long-term past PM exposures were associated with smaller deep-gray volumes overall, and higher PM2.5 exposures were associated with smaller brain volumes in the Minnesota site. Further work is needed to understand the sources of heterogeneity across sites. https://doi.org/10.1289/EHP2152
Foundation trainees warn of inadequate experience in emergency medicine
Authors: Henry Tudor Pole
Journal: BMJ (2013)

Doctors training at the foundation stage do not have enough exposure to emergency medicine and believe that the current assessment system does not identify failing trainees, concludes research published in the Journal of the Royal Society of Medicine .1

The survey of more than 1000 foundation trainees found that 37% spent five hours or less a week clerking emergency …
Abiraterone acetate (AA) plus prednisone (P) 5 mg QD in metastatic castration-naïve prostate cancer (mCNPC): Detailed safety analyses from the LATITUDE phase 3 trial.
Authors: Karim Fizazi, Namphuong Tran, Luis Enrique Fein, Nobuaki Matsubara, Anders Bjartell, Luca Galli, Jae-Lyun Lee, Danish Mazhar, Scott A. North, David Olmos, Henrik Suttmann, Qing Zou, Susan Li, Jason L. Martin, Youn C. Park, Giri Sulur, Kris Deprince, Peter De Porre, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

182 Background: AA + P added to androgen deprivation therapy (ADT) improves overall survival (OS) in newly diagnosed mCNPC patients (pts). AA has been previously coadministered with P (10 mg QD). As a lower dose of P (5 mg QD) was used in LATITUDE, we conducted additional safety analyses. Methods: 1199 pts with newly diagnosed, high-risk mCNPC (≥ 2 of 3 risk factors: Gleason ≥ 8, ≥ 3 bone lesions, visceral metastases) were randomized 1:1 to AA (1 gm QD) + P (5 mg QD) + ADT or placebos (PBOs) of AA and P + ADT: median treatment duration 24 and 14 mo, respectively. Safety analyses focused on key mineralocorticoid excess (ME)-related adverse events (AEs): hypertension (HTN) and hypokalemia. Results: Increased HTN with 5 mg/d P with AA + ADT (relative risk, 1.6 [95% CI, 1.4-1.9]) was similar to prior studies using 10 mg/d P (COU-AA-301: 1.4 [0.9-2.0]; COU-AA-302: 1.6 [1.2-2.1]). Of Gr 3/4 HTN events, 87% (109/126 [AA + P + ADT]) and 83% (52/63 [PBOs + ADT]) resolved to Gr ≤ 2. There were few cerebrovascular events: AA + P + ADT, 5; PBOs + ADT, 9. The protocol allowed increasing dose of P to 10 mg for ME-related AEs, but most Gr 3/4 HTN events were managed only by supplemental antihypertensives. Prior use of antihypertensives at study entry was predictive of Gr 3/4 HTN in both treatment arms (RR: 1.85; 95% CI, 1.14-3.01). Gr 3/4 hypokalemia increased with AA + P + ADT (10.4% [62/597]) vs PBOs + ADT (1.3% [8/602]); 89% (55/62) and 100% (8/8) of these events improved to Gr ≤ 2. Less than 1% of pts in either arm discontinued therapy for ME-related AEs. Conclusions: In-depth analysis of LATITUDE data confirms the safety of 5 mg/d P with AA + ADT and helps provide practical treatment guidance for managing mCNPC. Clinical trial information: NCT01715285. [Table: see text]
Editor’s Choice: A helping hand
Authors: Abi Rimmer
Journal: BMJ (2016)

Doctors’ working lives will always include periods when they need support and advice from others. Coaching is one form that this support could take, says Victoria Cleak (http://careers.bmj.com/careers/advice/A\_coach\_can\_improve\_the\_performance\_of\_any\_doctor). At a time when the profession is facing unprecedented stress, she says that more should be done to offer this resource to …
Diploma in otolaryngology, head and neck surgery (DO-HNS)
Authors: Hiba Al-Reefy
Journal: BMJ (2007)

TOP TIPS 

FURTHER INFORMATION 

Examinations and Assessment Department, The Royal College of Surgeons of England, 35-43 Lincoln's Inn Fields, London WC2A 3PE. dohns.exams@rcseng.ac.uk; 020 7869 6281.

Senior house …
Comment on Novodvorsky et al. Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes. Diabetes Care 2017;40:655–662
Authors: Philip Home, John Lachin
Journal: Diabetes Care (2018)

The article by Novodvorsky et al. (1) claims to show an incident rate ratio for bradycardia during periods of nocturnal hypoglycemia versus euglycemia of 6.44 (95% CI 6.26, 6.63). However, with only 37 people studied, and only a proportion of those having hypoglycemia and/or dysrhythmias, it would not be possible for such tight confidence limits to be anywhere near valid. A much larger study of longer duration would be required for this.

Further, it was not clear to us what proportions of the participants were included in the analysis as having hypoglycemia data with paired Holter electrocardiogram data and perhaps matching “euglycemia” data. Although the number of people and hours with dysrhythmias were …
IDENTIFYING RISK FACTORS FOR MASSIVE RIGHT VENTRICULAR DILATION IN PATIENTS WITH REPAIRED TETRALOGY OF FALLOT
Authors: Clinton Cochran, Lindsey Gakenheimer-Smith, Sunkyung Yu, Ray Lowery, Jimmy Lu, Maryam Ghadimi Mahani, Prachi Agarwal, Adam Dorfman
Journal: Journal of the American College of Cardiology (2018)
Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts
Authors: Benjamin J. Drapkin, Julie George, Camilla L. Christensen, Mari Mino-Kenudson, Ruben Dries, Tilak Sundaresan, Sarah Phat, David T. Myers, Jun Zhong, Peter Igo, Mehlika H. Hazar-Rethinam, Joseph A. Licausi, Maria Gomez-Caraballo, Marina Kem, Kandarp N. Jani, Roxana Azimi, Nima Abedpour, Roopika Menon, Sotirios Lakis, Rebecca S. Heist, Reinhard Büttner, Stefan Haas, Lecia V. Sequist, Alice T. Shaw, Kwok-Kin Wong, Aaron N. Hata, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber, Martin Peifer, Nicholas Dyson, Roman K. Thomas, Anna F. Farago
Journal: Cancer Discovery (2018)

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
Should statins be discontinued in cirrhosis with decompensation?
Authors: William Carey
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: I read with interest and enthusiasm the practice guidance by Chalasani et al. on the diagnosis and management of nonalcoholic fatty liver disease.1 Nearly all guidance statements are evidence‐based and helpful. I draw attention to and question the recommendation that statin use should be avoided in patients with (cirrhotic) decompensation. No evidence was provided demonstrating that statins are dangerous in decompensated cirrhosis, and I wonder if there is any. Given the widespread use of statins in those with fatty liver disease, this is a significant clinical issue. Multiple recent reports provide strong circumstantial evidence that statins decrease the rate of hepatic fibrosis, reduce the likelihood of hepatic decompensation, reduce portal pressure, and markedly reduce the risk of hepatocellular carcinoma. While it is true that most statin studies in liver disease are retrospective and do not specifically address those with decompensated cirrhosis, Abraldes et al. recently published a randomized prospective trial of addition of simvastatin to the management of patients with cirrhosis (including those with Childs B and C) who had survived an episode of variceal hemorrhage.2 Survival benefit accrued to those assigned to simvastatin. No hepatic adverse events due to statins were observed. In summary, in the absence of evidence of statin harm in decompensated cirrhosis and strong circumstantial evidence of benefit, do the authors believe it wise to interrupt statin administration at the first sign of decompensation? Is it ever reasonable to start a statin in such a patient?
THE EFFECT AND RELATIONSHIP OF AGE AND FRAILTY ON SURVIVAL IN PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Soroosh Kiani, Amanda Stebbins, Vinod H. Thourani, Jessica Forcillo, Sreekanth Vemulapalli, Andrzej Kosinski, Vasilis Babaliaros, David Cohen, Susheel K. Kodali, Ajay Kirtane, James Hermiller, James Stewart, Angela Lowenstern, Kreton Mavromatis, Michael J. Mack, Robert A. Guyton, Chandan Devireddy
Journal: Journal of the American College of Cardiology (2018)
COMPARING CORONARY ARTERY CALCIUM AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK SCORES IN DIABETIC, PREDIABETIC AND NONDIABETIC COMMUNITY BASED POPULATION WITHOUT KNOWN CARDIOVASCULAR DISEASE
Authors: Theresa Ratajczak, Arpan Patel, Amy Jiang, Saagar Sanghvi, Ronald Markert, Mukul Chandra
Journal: Journal of the American College of Cardiology (2018)
A novel glycocluster molecule prevents timothy‐induced allergic airway inflammation in mice
Authors: M. Lehto, H. Wolff, R. Leino, H. Alenius, J. Savolainen
Journal: Allergy (2018)

Abstract Background Allergen‐specific immunotherapy (SIT) effectively alleviates type I allergic diseases characterized by T helper (Th)2‐type immunity. Our recent studies have shown that a synthetic trivalent glycocluster, triacedimannose (TADM), suppresses the Th2‐type allergic inflammation. The aim of this study was to compare TADM with two well‐known adjuvants, unmethylated cytosine‐phosphate‐guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen‐induced chronic allergic inflammation model in mice. Methods Female BALB/c mice were intranasally sensitized with 50 μL of timothy grass pollen extract (TE) twice a week for a period of 15 weeks. Therapeutic intranasal treatments were then performed once a week after the tenth intranasal TE instillation using TADM (10 or 25 μg/50 μL), CpG‐ODN (20 μg/50 μL) or MPLA (2 μg/50 μL). Groups of 9‐10 animals per treatment were killed 24 hours after the last timothy dosage. Blood, bronchoalveolar lavage (BAL) fluids and lung biopsies were taken for subsequent analysis. Results When mice were repeatedly exposed to TE for 15 weeks, the number of eosinophils and lymphocytes increased in the BAL fluids. The eosinophil and lymphocyte counts decreased dose‐dependently and were practically abolished in the mice treated with TADM. Treatments with MPLA or CpG significantly increased the number s of neutrophils, while CpG nonsignificantly decreased eosinophilia compared to timothy exposure. Conclusions A novel synthetic glycocluster molecule inhibited the development of grass‐induced eosinophilic pulmonary inflammation in mice when administrated in the airways. This compound could be a candidate to be used either as an adjuvant in SIT or as a topical anti‐inflammatory treatment.
Is it better to do a clinical research fellow's post for one year or an LAT job (if available) for four to six months?
Authors: Eric Lim
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 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. www.bmjcareers.com/advicezone
Abstract 12002: Increasing Heart Rate in Left Bundle Branch Block Results in Incomplete Relaxation and Increases Left Ventricular Diastolic Stiffness
Authors: Oyvind S Andersen, Espen Boe, Helge Skulstad, Petter Storsten, Hans H Odland, Otto A Smiseth, Espen W Remme
Journal: Circulation (2015)

Introduction: Left bundle branch block (LBBB) slows LV pressure decay and shortens diastole. At low heart rates (HR) this may not compromise filling as diastolic duration is sufficient for complete relaxation. Purpose: We investigated if further abbreviation of diastole at increased HR could cause incomplete relaxation, particularly in the late activated LV lateral wall; thereby increasing diastolic LV stiffness, which may cause increased filling pressure. Methods: We analyzed data from a study of 10 canines where HR was increased from 120 to 140 by atrial pacing before and after induction of LBBB. Ventricular and pericardial pressures, LV volume and regional segment lengths (SL) were measured. Global diastolic stiffness was calculated from end diastolic (ED) transmural LV pressure-volume (PV) relations and regional stiffness from pressure-SL relations in septum and lateral wall. A mathematical model was used to estimate the increase in filling pressure due to incomplete relaxation at HR 160 and 180. Results: In LBBB, tau was prolonged and diastole abbreviated at both HR 120 and 140, compared to baseline (Fig. 1). Increased HR during LBBB stiffened the ventricle, seen as an upward shift of the ED PV relation by 1.4±1.7 mmHg (±SD), (p=0.03) whereas no shift (-0.9±1.5 mmHg) (NS) was seen at baseline (Fig. 2). Regional ED P-SL relations showed a larger upward shift of the lateral wall (1.1±1.8 mmHg) and hence a more pronounced stiffening compared to the septum (0.6±1.5 mmHg) (p&lt;0.05), indicating more delayed lateral wall relaxation. Mathematical estimation showed an increase in filling pressure of 7 and 16 mmHg due to further diastolic abbreviation at HR 160 and 180, respectively. Conclusions: LV diastolic stiffness is increased at high heart rates in LBBB due to incomplete relaxation, particularly of the late activated LV lateral wall. Diastolic stiffening by increased HR may lead to exercise intolerance and dyspnoea in LBBB patients due to elevated filling pressure.
Patient Commentary: “I don’t want to go to Switzerland, and I don’t want to attempt suicide”
Authors: Sarah Jessiman
Journal: BMJ (2018)

My name is Sarah Jessiman, and I’m a positive person doing my best to live well with terminal cancer at 51 years of age. I want to explain why I think doctors should support the campaign to legalise assisted dying in the UK. Perhaps this seems odd, coming from someone prepared to endure all kinds of arduous treatments to stay alive.

My reasons for wanting the choice of an assisted death are simple and shared by many patients in similar situations. I’m terrified of the sort of death I may have to face. I would draw huge comfort from knowing that I could say “enough” …
Editor’s Choice: Making the grade
Authors: Abi Rimmer
Journal: BMJ (2016)

Moving from the foundation programme into specialty training can be an exciting and stressful time. The application process itself is multifaceted, and gathering evidence for the application form and portfolio can be the most time consuming part of the process.

However, as Nilofer Husnoo and M Shaan Goonoo explain this week, little …
Practice-based evidence for factors associated with urinary incontinence following prostate cancer care.
Authors: Kevin Li, Christopher J. Magnani, Selen Bozkurt, Tina Seto, Douglas W. Blayney, James D. Brooks, Tina Hernandez-Boussard
Journal: Journal of Clinical Oncology (2018)

106 Background: Urinary incontinence (UI) is a common complication following treatment for localized prostate cancer. Past studies evaluating UI risk factors use surveys or chart abstraction, which may be costly and lack generalizability. Electronic health records (EHR) allow us to examine UI at a population level. We applied data mining methods to EHR data to: (1) evaluate rates of UI following prostate cancer treatment; and (2) evaluate potential risk factors for posttreatment UI. Methods: We conducted a retrospective analysis of patients undergoing prostatectomy or radiation therapy for localized prostate cancer between 2009-2016, and who received follow-up care at our medical center. Our cohort was constructed from the institutional EHR and the California Cancer Registry. The primary outcome was the presence of UI, measured in three-month intervals from the start of first-line treatment. The secondary outcome was UI 12-24 months following treatment (“late UI”). UI was assessed using natural language processing of EHR clinician notes. UI was also assessed with the EPIC-26 quality of life survey, which a subset of patients had prospectively completed. Results: Our cohort consisted of 2783 men, of whom 1907 (69%) underwent surgery and the remainder received radiation; of this cohort, 609 (22%) had data on late UI status. UI prevalence was higher among surgery than radiation patients across all posttreatment time points, and 278 of 434 (64%) surgery patients had late UI compared to 78 of 175 (45%) radiation patients (p &lt; 0.001). Univariable analyses showed an association between pretreatment and late UI among surgery patients as measured in the EHR (OR 2.5, 95% CI 1.0-6.5, p = 0.05) and by EPIC-26 (OR 8.1, 95% CI 1.8-36.5, p = 0.01). Only surgery (compared to radiation) was a significant predictor of late UI (OR 5.8, 95% CI 1.1-32.3, p = 0.05) in multivariable regression with EHR data. Conclusions: Using EHR data, we found that treatment modality was a significant predictor of late UI among prostate cancer patients who underwent prostatectomy or radiation therapy. These results suggest the utility of EHRs in patient-centered outcomes research in prostate cancer care, and should be validated at other sites.
Erratum. The National Diabetes Education Program at 20 Years: Lessons Learned and Plans for the Future. Diabetes Care 2018;41:209–218
Authors: Linda M. Siminerio, Ann Albright, Judith Fradkin, Joanne Gallivan, Jude McDivitt, Betsy Rodríguez, Diane Tuncer, Faye Wong
Journal: Diabetes Care (2018)

In the article cited above, the affiliation for author Faye Wong was incorrect. Ms. Wong’s …
I am thinking of working in the Persian Gulf for a couple of years, after completing my time as a preregistration house officer. If I did this, would it be difficult to get a good job when I came back to the United Kingdom?
Authors: Nick Banatvala
Journal: BMJ (2004)

<i>Got 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.</i>
Health secretary orders clampdown on very senior managers’ pay
Authors: Caroline White
Journal: BMJ (2015)

The health secretary for England, Jeremy Hunt, has told the NHS to justify why any new very senior manager should be paid more than the prime minister.

The instruction, which requires NHS officials to write to the Department of Health with a justification, is part of a crackdown on profligacy and waste in the health service. Department of Health figures show that more than a fifth of directors in the health service currently earn more than £142 500, the salary paid to David Cameron.

In a letter sent to chiefs of hospitals and clinical commissioning groups on 2 June, Hunt said that reform of salary arrangements for NHS staff was “a very high priority and must include a review of the pay of the most senior staff in the NHS—chief executives and executive directors.” He continued, “Although these staff do important jobs and deserve to be fairly rewarded, it is vital that we do not lose sight of the …
Structural basis of DUX4/IGH-driven transactivation
Authors: Xue Dong, Weina Zhang, Haiyan Wu, Jinyan Huang, Ming Zhang, Pengran Wang, Hao Zhang, Zhu Chen, Sai-Juan Chen, Guoyu Meng
Journal: Leukemia (2018)

Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERGalt through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNADRE-bound DUX4HD2 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox. These mutations, when introduced into DUX4/IGH, abrogated its transactivation activity in Reh cells. More importantly, the structure-based mutants significantly impaired the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. All these results help to define a key DUX4/IGH-DRE recognition/step in B-ALL.