tbuckley/cabot-search huggingface dataset:
Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ
Authors: Yang Yu, Hongwei Du, Shengnan Wei, Linjing Feng, Junnan Li, Fan Yao, Ming Zhang, Grant M Hatch, Li Chen
Journal: Theranostics (2018)

The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle. Methods: The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3-L1 adipocytes. Results: We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a-mediated repression of PPARγ and its downstream genes involved in the development of obesity. Conclusions: These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.
HEMODYNAMIC DURABILITY OF TRANSCATHETER AORTIC VALVES USING THE UPDATED VALVE ACADEMIC RESEARCH CONSORTIUM-2 CRITERIA
Authors: Arnav Kumar, Kimi Sato, Vivek Menon, Kinjal Banerjee, Jyoti Narayanswami, Jorge Betancor, Divyanshu Mohananey, Abhishek Sawant, Abdur Khan, Anil Kumar Reddy Anumandla, Amar Krishnaswamy, E. Murat Tuzcu, Wael Jaber, Stephanie Mick, Lars Svensson, Eugene Blackstone, Zoran Popovic, Samir Kapadia
Journal: Journal of the American College of Cardiology (2018)
Data sharing and reanalysis of randomized controlled trials in leading biomedical journals with a full data sharing policy: survey of studies published in<i>The BMJ</i>and<i>PLOS Medicine</i>
Authors: Florian Naudet, Charlotte Sakarovitch, Perrine Janiaud, Ioana Cristea, Daniele Fanelli, David Moher, John P A Ioannidis
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objectives</h3> To explore the effectiveness of data sharing by randomized controlled trials (RCTs) in journals with a full data sharing policy and to describe potential difficulties encountered in the process of performing reanalyses of the primary outcomes. <h3>Design</h3> Survey of published RCTs. <h3>Setting</h3> PubMed/Medline. <h3>Eligibility criteria</h3> RCTs that had been submitted and published by <i>The BMJ</i> and <i>PLOS Medicine</i> subsequent to the adoption of data sharing policies by these journals. <h3>Main outcome measure</h3> The primary outcome was data availability, defined as the eventual receipt of complete data with clear labelling. Primary outcomes were reanalyzed to assess to what extent studies were reproduced. Difficulties encountered were described. <h3>Results</h3> 37 RCTs (21 from <i>The BMJ</i> and 16 from <i>PLOS Medicine</i>) published between 2013 and 2016 met the eligibility criteria. 17/37 (46%, 95% confidence interval 30% to 62%) satisfied the definition of data availability and 14 of the 17 (82%, 59% to 94%) were fully reproduced on all their primary outcomes. Of the remaining RCTs, errors were identified in two but reached similar conclusions and one paper did not provide enough information in the Methods section to reproduce the analyses. Difficulties identified included problems in contacting corresponding authors and lack of resources on their behalf in preparing the datasets. In addition, there was a range of different data sharing practices across study groups. <h3>Conclusions</h3> Data availability was not optimal in two journals with a strong policy for data sharing. When investigators shared data, most reanalyses largely reproduced the original results. Data sharing practices need to become more widespread and streamlined to allow meaningful reanalyses and reuse of data. <h3>Trial registration</h3> Open Science Framework osf.io/c4zke.
THE DEVELOPMENT AND EFFICACY OF A PEDIATRIC CARDIOLOGY FELLOWSHIP ONLINE PREPARATORY COURSE
Authors: Kara Motonaga, Loren Sacks, Inger Olson, Sowmya Balasubramanian, Sharon Chen, Lynn Peng, Jeffrey Feinstein, Norman Silverman, Frank Hanley, David Axelrod, Catherine Krawczeski, Scott Ceresnak
Journal: Journal of the American College of Cardiology (2018)
Single-arm phase ib/II study of durvalumab and guadecitabine in advanced kidney cancer (NCT03308396).
Authors: Sarah Elizabeth Yentz, Melissa Andrea Reimers, Monika Joshi, Yousef Zakharia, Shilpa Gupta, Eric A. Singer, Stephanie Daignault, Weiping Zou, Dana Musapatika, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2018)

TPS711 Background: Checkpoint inhibitor immunotherapy directed at PD1/PDL1 has shown clinical efficacy in advanced clear cell Renal Cell Cancer (ccRCC). However, only a minority of patients respond to anti-PD1 monotherapy. There is an urgent unmet need to improve response rates including through rational combinations to reverse immune evasion by tumors. The chemokines CXCL9 and CXCL10 in the tumor micro-environment are chemo-attractants for activated NK and Th1 cells and are critical for anti-tumor immunity. Preclinical data from our group showed hypermethylation induced silencing of CXCL9/10 signaling is an important tumor immune evasion mechanism. In RCC cell lines (A-498, HTB-46 and CRL-1611), hypomethylating agents increased CXCL9/10. In mouse xenograft models, combination therapy with a hypomethylating agent and checkpoint inhibitors led to higher levels of CXCL 9/10, reversal of immune evasion and potent tumor regression. We hypothesized that the combination of guadecitabine (hypomethylating agent) with durvalumab (anti-PDL1 antibody) would increase T lymphocyte infiltration into RCC tumors including those that are immunologically ‘cold’ and result be effective in 1 st and 2 nd line RCC. Methods: The study is a single arm, multi-site, phase 1b/2 trial through the Big Ten Cancer Research Consortium of Guadecitabine (starting dose of 60 mg/m2/dose subcutaneously on days 1-5) with Durvalumab (1500 mg IV on day 8) in 28-day cycles in pts with metastatic ccRCC. Cohort 1 (N = 36) will consist of pts naïve to checkpoint inhibitor immunotherapy and 0-1 prior therapies. Cohort 2 (N = 16) will include pts who did not respond to prior anti-PD-1/PD-L1 therapy. The primary endpoint is objective response rate by RECIST 1.1 in cohort 1. Statistical analysis will use a binomial exact test to compare the ORR proportion in patients treated in Cohort 1 with the combination compared to an expected proportion of 25% with anti-PDL1 alone. The extensive correlative objectives include serial evaluation of serum CXCL9/10 levels and LINE-1 methylation status as well as tumor infiltrating lymphocytes profiling, PD-L1 expression, tumor mutational burden and NGS on mandatory baseline and optional biopsies at progression. Clinical trial information: NCT03308396.
Will MACRA Improve Physician Reimbursement?
Authors: Gail R. Wilensky
Journal: New England Journal of Medicine (2018)

Interview with Dr. Gail Wilensky on physician payment under MACRA and efforts to improve health care outcomes and value. (11:20)Download The Medicare Payment Advisory Commission, doubting that current law will move Medicare toward value-based physician reimbursement, has proposed scrapping the Merit-Based Incentive Payment System, among other changes. But there are problems with its recommended fixes.
Is it possible to decline (with six weeks' notice) a senior house officer job which I originally accepted? If so, how should I limit any damage?
Authors: Trevor Pickersgill
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>
SOFA: Study of omega-3 fatty acids and ventricular arrhythmia. A multicenter, randomized clinical trial.
Authors: I.A. Brouwer, P.L. Zock, A.J. Camm, D. Bocker, R.N.W. Hauer, E.F.D. Wever, C. Dullemeijer, J.E. Ronden, M.B. Katan, E.G. Schouten
Journal: Circulation (2006)
Clinical characters and prognostic factors of young female patients (pts) with metastatic gastric adenocarcinoma (GC).
Authors: Yanshuo Cao, Xiaotian Zhang, Jian Li, Jifang Gong, Ming Lu, Zhihao Lu, Xicheng Wang, Jun Zhou, Jie Li, Yan Li, Lin Shen
Journal: Journal of Clinical Oncology (2018)

133 Background: GC is one of the most common cancers worldwide, and has an even higher incidence rate in China. The incidence rate of GC is rising in young pts (≤ 40 years). Previous studies suggested that the percentage of female pts was higher in young pts than that in older pts. The clinical characters and potential prognostic factors have not been well described for young female pts with metastatic GC. Methods: A retrospective chart review was conducted for all GC pts treated at our institution from 1995 to 2012. Pt demographics, clinical characters, treatment related information and survival data were collected. Kaplan-Meier test was used for the survival analysis. Cox regression was conducted for uni- and multi-variate analysis. Results: In total, 1,862 pts with histologically confirmed GC were identified. Among these pts, 11.3% were young pts when first diagnosed. The male to female ratio was 2.76:1 for the whole group and 1:1.02 for young pts. Ninety-eight female pts were ≤ 40 years when diagnosed of metastatic GC. For this group, median age was 35 years (range: 19-40 years). Seventy-one (72.4%) had &gt; 1 metastatic sites, and 85 (86.7%) received palliative chemotherapy. The median overall survival (OS) was 14.9 months (95% confidence interval [CI] 11.8-18.0 months). Seventy-six (77.6%) pts had intact primary tumor when diagnosed of metastatic disease. Compared to 22 pts who relapsed after radical surgery, OS was similar for pts presented with de novo metastatic disease (Hazard Ratio (HR) 1.03, 95% CI: 0.55 to 1.92, P= 0.9). Of these 76 pts, 36 underwent palliative gastric resection, which was associated with improved OS (15.3 vs. 9.0 months; HR 0.37, 95% CI: 0.19 to 0.74, P = 0.003). Forty-six (46.9%) pts had ovarian metastasis, and 20 had oophorectomy. Palliative oophorectomy was associated with significantly improved OS (36.6 vs. 12.4 months, HR 0.34, 95% CI: 0.14 to 0.80, P = 0.013). Conclusions: There was an increased ratio of females in young GC pts. In young female pts with metastatic GC, palliative resection of gastric primary and ovarian metastasis were associated with significantly improved OS, and should be considered in appropriate pts.
PROGNOSTIC VALUE OF HIGH SENSITIVE TROPONIN IN STABLE CORONARY ARTERY DISEASE
Authors: Rocío Carda, Oscar Lorenzo, Ana Maria Pello, Álvaro Aceña, Carlos Gutierrez Landaluce, Carmen Cristobal, Nieves Tarín, Ana Huelmos, Jesús Fuentes-Antras, María Martín Mariscal, Ignacio Hernandez Gonzalez, Ana Huelmos, Lorenzo Lopez Bescos, José Tunon
Journal: Journal of the American College of Cardiology (2018)
Surgeons urged not to ignore poor care in new whistleblowing guidance
Authors: Helen Jaques
Journal: BMJ (2013)

The Royal College of Surgeons has advised its members not to “bury their heads in the sand” but to speak up when they spot examples of poor care.

The college’s new guidance— Acting on Concerns: Your Professional Responsibility —recommends that surgeons should not wait for weaknesses in care to turn into full blown …
Intensity of exposure to pulmonary tuberculosis determines risk of tuberculosis infection and disease
Authors: Carlos Acuña-Villaorduña, Edward C. Jones-López, Geisa Fregona, Patricia Marques-Rodrigues, Mary Gaeddert, Carolina Geadas, David Jamil Hadad, Laura F. White, Lucilia Pereira Dutra Molina, Solange Vinhas, Rodrigo Ribeiro-Rodrigues, Padmini Salgame, Moises Palaci, David Alland, Jerrold J. Ellner, Reynaldo Dietze
Journal: European Respiratory Journal (2018)

Household contacts of pulmonary tuberculosis (TB) patients are at increased risk of TB infection and disease. However, their risk in relation to the intensity of exposure remains unknown.We studied smear-positive TB cases and their household contacts in Vitória, Brazil. We collected clinical, demographic and radiographic information from TB cases, and obtained tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT) results from household contacts. We measured intensity of exposure using a proximity score and sleep location in relation to the TB index case and defined infection by TST ≥10 mm or QFT ≥0.35 UI·mL-1 We ascertained secondary TB cases by reviewing local and nationwide case registries.We included 160 TB index cases and 894 household contacts. 464 (65%) had TB infection and 23 (2.6%) developed TB disease. Risk of TB infection and disease increased with more intense exposures. In an adjusted analysis, the proximity score was associated with TB disease (OR 1.61, 95% CI 1.25-2.08; p<0.000); however, its diagnostic performance was only moderate.Intensity of exposure increased risk of TB infection and disease among household contacts; however, its diagnostic performance was still suboptimal. A biomarker to target preventive therapy is urgently needed in this at-risk population.
Preventing violence against conflict-affected adolescent girls: findings from Ethiopia, Democratic Republic of Congo, and Pakistan
Authors: Lindsay Stark, Khudejha Asghar, Ilana Seff, Gary Yu, Asham Assazenew Baysa, Kathryn Falb
Journal: The Lancet Global Health (2018)

BackgroundInterpersonal violence is a major public health concern in humanitarian contexts, and adolescent girls are uniquely vulnerable. There is little evidence on effective violence prevention programmes targeting this population. We investigated the efficacy, feasibility, and acceptability of a life skills and safe spaces programme to reduce violence exposure for conflict-affected adolescent girls.MethodsEvaluations were conducted in Ethiopia, the Democratic Republic of Congo (DRC), and Pakistan. In Ethiopia and DRC, the programme was evaluated via cluster-randomised controlled trials in refugee camps. In Ethiopia, girls aged 13–19 were enrolled. Girls and their caregivers in the treatment group received the intervention and the control group was waitlisted. In DRC, girls aged 10–14 and their caregivers were enrolled. All girls received the intervention and treatment was randomised for caregivers. In both Ethiopia and DRC, the primary outcome was girls' exposure to sexual violence. In Pakistan, a mixed-methods evaluation design focused on feasibility and acceptability. A single-group within-participants pre-post test was administered to 78 internally displaced and host community girls aged 12–19 enrolled in the programme. Qualitative in-depth interviews were conducted with a subset of 15 girls at endline. Primary outcomes included perceptions of programme content and changes in freedom of movement, safety, self-esteem, and hope.FindingsIn Ethiopia, 919 girls were enrolled, 457 in the intervention group and 462 in the wait-list group. At 12-month follow-up, the intervention was not significantly associated with reduction in exposure to sexual violence (aOR=0·96, 95% CI 0·59–1·57). In DRC, 869 girls ages 10–14 and 764 caregivers were enrolled. 389 caregivers received the intervention and 375 were wait-listed. At 12-month follow-up, the intervention was not significantly associated with reduction in exposure to sexual violence (aOR=0·95, 95% CI 0·65–1·37). In Pakistan, programme content was perceived as acceptable and freedom of movement, safety, self-esteem, and hope increased over time.InterpretationThe intervention was feasible and acceptable in Pakistan, but further research and programmatic adaptations are needed to prevent adolescent violence in humanitarian contexts.FundingUK Department for International Development.
Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases
Authors: E.E. Vokes, N. Ready, E. Felip, L. Horn, M.A. Burgio, S.J. Antonia, O. Arén Frontera, S. Gettinger, E. Holgado, D. Spigel, D. Waterhouse, M. Domine, M. Garassino, L.Q.M. Chow, G. Blumenschein, F. Barlesi, B. Coudert, J. Gainor, O. Arrieta, J. Brahmer, C. Butts, M. Steins, W.J. Geese, A. Li, D. Healey, L. Crinò
Journal: Annals of Oncology (2018)

BackgroundLong-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC.Patients and methodsPatients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses.ResultsAfter 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%).ConclusionsAfter 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated.Clinical trial registrationCheckMate 017: NCT01642004; CheckMate 057: NCT01673867.
Immune and molecular determinants of response to neoadjuvant chemotherapy in inflammatory breast cancer.
Authors: Sangeetha Meda Reddy, Jennifer Ann Wargo, Alexandre Reuben, Michael T. Tetzlaff, Jason Roszik, James M. Reuben, Wendy A. Woodward, Naoto T. Ueno, Savitri Krishnamurthy, Elizabeth Ann Mittendorf
Journal: Journal of Clinical Oncology (2017)

11501 Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer and has poor responses to standard of care neoadjuvant chemotherapy (NAC). Given there is a limited understanding of the immune microenvironment of IBC, this study aims to characterize the immune and molecular profiles of stage III and IV IBC and to identify biomarkers of response to treatment and targets for future therapies. Methods: IBC patients with available pre-treatment tumor samples and with intent to take to mastectomy were identified in the IBC tumor registry and tissue bank. Tumor infiltrating lymphocyte (TIL) infiltration in the tumor stroma was quantified on H&amp;E slides per consensus guidelines (n = 91). On a subset of patients with available samples, deeper immune profiling was performed, including quantification of CD8 T cells by immunohistochemistry (IHC) (n = 33), PD-L1 tumor expression by IHC (n = 14), myeloid cells by multiplex IHC (n = 15), T cell clonality by T cell receptor sequencing (n = 22), and total mutational load (TML) by whole exome sequencing (n = 20). Results: Mean TIL were higher in tumors from patients that achieved a pathological complete response (pCR) to NAC than from those that did not (13.79 vs 7.24%, p = 0.019) and in patients with stage III compared to stage IV disease (11.90 vs 4.79%, p &lt; 0.001). Though no statistically significant differences in CD8 infiltrate by response, stage, or receptor status were seen, the presence of a more clonal T cell population was predictive of pCR (13.27 vs 5.70% top 5 clone frequency, p = 0.042 among stage III patients). Myeloid cell staining revealed that tryptase staining, indicative of mast cells, was inversely associated with pCR (28.26 vs 108.0 counts/mm2, p = 0.011). Three of fourteen patient tumors displayed low PD-L1 tumor positivity (range 1-2%, 1+-2+) with the others being negative. Genomic profiling showed no statistically significant differences in TML by stage, receptor status, response, or immune infiltrate. Conclusions: Higher TIL, more clonal T cells, and lower mast cell infiltration are predictive of response to NAC in IBC. Comprehensive immune characterization of a larger cohort of pre- and post-treatment samples is currently underway.