tbuckley/cabot-search huggingface dataset:
PROSPECTIVE ASSESSMENT OF THE MISSION: LIFELINE PREACT-STEMI ALGORITHM TO REDUCE FALSE ACTIVATION OF THE CARDIAC CATHETERIZATION LABORATORY
Authors: Kelsey L. Baran, David Lange, Andrew Ajoku, Joseph Abraham Kavian, David Hildebrandt, Michael C. Kontos, Mic Gunderson, William French, Timothy D. Henry
Journal: Journal of the American College of Cardiology (2018)
Threat of delayed revalidation must not be used to impose job plans, says BMA
Authors: Abi Rimmer
Journal: BMJ (2015)

Hospital trusts must not threaten to delay consultants’ revalidation or postpone their appraisal to force them to accept an unfavourable job plan, the BMA has said. 

Delegates at the BMA’s annual UK consultants’ conference in London on Wednesday 4 March voted unanimously in favour of a motion saying that any NHS organisation found to be doing so “must be suitably penalised.” …
Facing the Shortage of IV Fluids — A Hospital-Based Oral Rehydration Strategy
Authors: Andrés M. Patiño, Regan H. Marsh, Eric J. Nilles, Christopher W. Baugh, Shada A. Rouhani, Stephanie Kayden
Journal: New England Journal of Medicine (2018)

Facing the Shortage of IV Fluids Emergency departments are substantial consumers of IV fluids, so in the face of the worsened U.S. saline shortage, a hospital ED team developed an oral rehydration protocol for patients with mild dehydration that has since been adopted hospital-wide.
Social media and apps can benefit medical learning, academics say
Authors: Matthew Limb
Journal: BMJ (2015)

Technology can benefit medical learning, but more evidence is needed to show what trainee doctors gain from using smartphone apps and social media, researchers have said.

In a review article, published in Postgraduate Medical Journal , academics from Cardiff University’s School of Social Sciences said there was no doubt that technology could “facilitate” both knowledge acquisition and social participation in postgraduate medical education.1 “But there remains a need to better understand the value it adds, and not just in terms of efficiency,” they said. “We need to study how it facilitates the transformation of learning outcomes and interprofessional relationships and where it can be …
Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes
Authors: Y. Kim, J.Y. Cho, S.W. Oh, M. Kang, S.E. Lee, E. Jung, Y.S. Park, J. Lee
Journal: British Journal of Dermatology (2018)

Adiponectin is an adipocyte‐derived cytokine that circulates as a full‐length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full‐length adiponectin. To examine the involvement of gAd in melanogenesis and its mechanisms of action. The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia‐associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd‐mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element‐binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate‐activated protein kinase (AMPK)–p38 mitogen‐activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK–p38 MAPK–CREB pathway. These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology.
Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Long-term survival, quality-adjusted survival, and cost-effectiveness analysis.
Authors: Nicholas James, Beth Woods, Eleftherios Sideris, Melissa Ruth Spears, David P. Dearnaley, Malcolm Mason, Noel Clarke, Mahesh K B Parmar, Matthew Robert Sydes, Mark Sculpher
Journal: Journal of Clinical Oncology (2018)

162 Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( &gt; 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients. Clinical trial information: ISRCTN78818544.
Gerald “Jerry” M Reaven: the “father of insulin resistance”
Authors: Bob Roehr
Journal: BMJ (2018)

Gerald “Jerry” M Reaven was a pioneer in insulin research, whose discoveries formed the basis of the concept of metabolic syndrome. He is credited with developing the first quantitative method to measure insulin mediated glucose uptake in humans (1970). He used this tool to establish the importance of insulin resistance in human disease, most notably type 2 diabetes. He also showed how insulin had a role in cardiovascular disease in people who do not have diabetes.

Reaven first laid out his framework for syndrome X, the role of insulin resistance in human disease, in a lecture in 1988, when he received the Banting medal for scientific achievement, the highest honour awarded by the American Diabetes Association.1 The condition would later become more commonly known as metabolic syndrome.

“There’s not one shred of evidence that insulin resistance causes obesity,” Reaven combatively wrote. “Insulin resistance means that insulin isn’t acting correctly. So if you don’t have enough insulin or if your cells aren’t responding to insulin, you can’t deposit glucose into cells. If anything, you would lose weight.” Furthermore, excessive insulin could damage the …
Transient elastography is an unreliable marker of liver fibrosis in patients with portal vein thrombosis
Authors: Ruiyao Huang, Zu‐Hua Gao, An Tang, Giada Sebastiani, Marc Deschenes
Journal: Hepatology (2018)

Huang, Ruiyao; Gao, Zu‐Hua; Tang, An; Sebastiani, Giada; Deschenes, Marc Author Information
Is Sorafenib an Optimal Treatment for Hepatocellular Carcinoma With Macrovascular Invasion or Metastatic Disease?
Authors: Xiu‐Ping Zhang, Kang Wang, Wei‐Xing Guo, Zhen‐Hua Chen, Shu‐Qun Cheng
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. Supported by the Key Project of Natural Science Foundation of China (no.: 81730097); the grants of the Science Fund for Creative Research Groups (no.: 81521091); Chang Jiang Scholars Program (2013) of China Ministry of Education; the National Key Basic Research Program "973 project" (no.: 2015CB554000); Shanghai Municipal Health Bureau (no.: SHDC12015106); Shanghai Science and Technology Committee (no.: 134119a0200). Author names in bold designate shared co‐first authorship. TO THE EDITOR: We read with great interest the article by Finn et al. in Hepatology,1 which explored therapies for advanced hepatocellular carcinoma (HCC) with macrovascular invasion or metastatic disease, applying a systematic review and meta‐analysis. They reported that in advanced HCC patients with Child‐Pugh A liver function, sorafenib is the only recommended treatment. Several observational studies evaluated locoregional therapies alone or in combination with other treatments, but were limited by a very low quality of evidence. The investigators' conclusion echoes official guidelines in the United States and Europe, where oral sorafenib was the only recommended treatment for advanced HCC patients.2 Based on the above, we would like to make the following comments. First, some investigators have recommended surgical treatment for selected patients with macrovascular invasion.3 Liver resection (LR) is associated with a longer survival outcome than nonsurgical treatment in patients with portal vein tumor thrombus (PVTT). Similarly, patients with hepatic vein tumor thrombus (HVTT) have a better prognosis in patients with HVTT under LR. Given recent advances in perioperative nursing and surgical operation, surgery may be the first choice for some selected advanced HCC patients with macrovascular invasion. Second, this systematic review may not include all observational studies for therapies for advanced stage HCC patients because of different inclusion criteria and included time periods. Another meta‐analysis concluded that LR may lead to longer overall survival for HCC patients with PVTT than transarterial chemoembolization.5 In addition, some multidisciplinary combined therapies other than only oral sorafenib had a better prognosis in HCC patients with extrahepatic metastasis. In summary, this meta‐analysis by Finn et al. a strong contribution that focuses on therapies for advanced HCC with macrovascular invasion or metastatic disease. Because of a low quality of evidence from several observational studies, it is vital to design high‐quality multicenter, randomized, controlled trials to assess multidisciplinary combined diagnosis and treatment, instead of only sorafenib, in some selected patients with advanced HCC that includes macrovascular invasion or metastatic disease.
Needle-shaped ultrathin piezoelectric microsystem for guided tissue targeting via mechanical sensing
Authors: Xinge Yu, Heling Wang, Xin Ning, Rujie Sun, Hassan Albadawi, Marcela Salomao, Alvin C. Silva, Yang Yu, Limei Tian, Ahyeon Koh, Chan Mi Lee, Aditya Chempakasseril, Peilin Tian, Matt Pharr, Jianghong Yuan, Yonggang Huang, Rahmi Oklu, John A. Rogers
Journal: Nature Biomedical Engineering (2018)
SUBCLINICAL ATHEROSCLEROSIS AND CORONARY ARTERY CALCIUM SCORES IN PATIENTS WITH COARCTATION OF THE AORTA
Authors: Yamini Krishnamurthy, Ada C. Stefanescu Schmidt, Daniel O. Bittner, Jan-Erik Scholtz, Amy Bui, Rajesh Reddy, Mohamed Youniss, Kendall Donohoe, Laura Flannery, Akl Fahed, Brian Ghoshhajra, Doreen Defaria Yeh, Ami Bhatt
Journal: Journal of the American College of Cardiology (2018)
Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study.
Authors: Daniel Peter Petrylak, David C. Smith, Thomas W. Flaig, Jingsong Zhang, Srikala S. Sridhar, Joseph D. Ruether, Elizabeth R. Plimack, Jaime R. Merchan, David I. Quinn, Deepak Kilari, Sandy Srinivas, Joaquina Celebre Baranda, Joshua Michael Lang, Matthew I. Milowsky, Matt D. Galsky, Alexander I. Spira, Elaina M. Gartner, Chunzhang Wu, Amal Melhem-Bertrandt, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2018)

431 Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was &lt; 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999.
Targeting autophagy and immunotherapy with hydroxychloroquine and interleukin 2 in patients with metastatic renal cell carcinoma (mRCC): A Cytokine Working Group study.
Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel Paul Normolle, Marc S. Ernstoff, Rahul Atul Parikh, David F. McDermott, Paul Monk, Thomas Olencki, David Friedland, Jodi Kathleen Maranchie, Lisa Helene Butterfield, Xiaoyan Liang, Michael T. Lotze
Journal: Journal of Clinical Oncology (2018)

106 Background: We performed a Phase II study of the combination of the autophagy inhibitor, hydroxychloroquine (HCQ), along with high dose IL-2 in patients with advanced renal cancer. 31 patients were entered on this Cytokine Working Group Study conducted at six member institutions;NCT01550367. This combination in murine models was associated with diminished toxicity and increased efficacy, and, in preliminary studies, diminished high mobility group box 1 (HMGB1) protein, consistent with its established role in serving as a Damage Associated Molecular Pattern (DAMP) molecule and inducer of autophagy. Methods: The Study Design involved initiating oral Hydroxychloroquine 300 mg P.O bid. Aldesleukin (600,000 IU/kg) was administered q8hrs in courses consisting of two cycles separated by 7-14 days and constituting a single course. For patients with stable or responsive disease, additional courses were administered every approximately 85-90 days. Serum, plasma, Paxgene tubes, and peripheral blood mononuclear cells were obtained sequentially prior to therapy initiation and sequentially on D1 and D2 of each cycle following initiation of therapy. Results: 31 patients (9F, 22M) have been registered and 3 confirmed complete responses observed; the current median overall survival has not been reached in the 29pts. The Baseline Karnofsky Score of 100 (17pts), 90 (13pts), and 80(1 pt). The mean age was 57.5 years, range = (45.2, 68.8). 26 patients had a mean of 12.5 doses +/-4.7 (3, 23) with 13 pts receiving a second course and 4, a third. Platelet nadir was diminished from baseline by 26%. Of the 27 patients in the data set, 18 had at least one Grade 4 toxicity at least possibly related to treatment, and 9 patients had at least one Grade 3 adverse event at least possibly related to treatment but no Grade 4 events.Serologic and cellular data and complete clinical data will be submitted with the completed abstract. Conclusions: The combination of high dose aldesleukin and daily oral HCQ was well tolerated. We have concluded this trial and will report mature survival data, toxicity data, and biomarkers/autophagy measures with the final submission. Clinical trial information: NCT01550367.
CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges
Authors: Stephen J Bagley, Arati S Desai, Gerald P Linette, Carl H June, Donald M O’Rourke
Journal: Neuro-Oncology (2018)

In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.
Intergroup study EORTC-1532-gucg: A phase 2 randomized open-label study of oral darolutamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive prostate cancer (PCa).
Authors: Bertrand F. Tombal, Silke Gillessen, Yohann Loriot, Sandrine Marreaud, Laurence Collette, Fred Saad
Journal: Journal of Clinical Oncology (2018)

TPS406 Background: Androgen deprivation therapy (ADT) by LHRH analogues aims to lower serum testosterone. ADT is associated with several side effects that include hot flushes, depression, loss of libido, metabolic disturbances leading to an increase risk of cardiovascular disease, increased bone resorption leading to increased risk of osteoporosis and skeletal fracture. AR antagonists may circumvent these side effects by suppressing AR transcription by competitive inhibition of AR, without lowering systemic testosterone. In Europe, first generation AR antagonists bicalutamide 150 mg is registered for the treatment of non-metastatic hormone-naïve PCa. is a novel AR antagonist that is structurally distinct with higher AR-binding affinity compared to bicalutamide, enzalutamide, and apalutamide. The aim of this trial is to investigate the activity, safety and tolerability of darolutamide as single agent, as an alternative to LHRH analogues in men requiring ADT. Methods: EORTC-1532-GUCG (NCT02972060) will randomize 250 men with hormone-naïve PCa 1:1 to 600 mg (2× 300-mg tablets) bid of darolutamide1 or LHRH agonist or antagonist, stratified for type of ADT (agonist vs. antagonist), disease extent (measurable, non-measurable, vs. no metastasis) and age (≥70 vs &lt; 70 years). Key inclusion criteria include histologically confirmed asymptomatic PCa (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks. Patients with up to 4 confirmed not visceral metastases, are allowed. Baseline total testosterone should be ≥ 8 nmol/L or 230 ng/dL. Primary endpoint is PSA response assessed at 24 weeks, defined as a ≥ 80% decline in PSA at week 24 in the darolutamide study arm. The ADT arm is used as an internal non comparative control. Key secondary endpoints include: Change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks (comparison between arms); objective response rate at 24 weeks in patients with measurable disease at baseline, safety according to NCI-CTC version 4.0. Clinical trial information: NCT02972060.
Clinical negligence claims could rise substantially, warns MPS
Authors: Abi Rimmer
Journal: BMJ (2017)

The cost of clinical negligence claims could rise to £2.6bn a year by 2022 in England if spending continues to increase at its current rate, the Medical Protection Society has warned.

In a report published on Friday 23 June the MPS called for legal reforms to control the cost of clinical negligence claims.1 It said that the amount paid out in claims by NHS Resolution, the organisation that provides indemnity schemes for NHS organisations in England, had risen by 72% in five years. If this trajectory continued for the next five years, the yearly bill to the NHS could increase from £1.5bn to £2.6bn, the MPS said.

Recent changes to the personal injury discount rate—the percentage rate that successful claimants in personal …
Germline pathogenic variants in patients with pheochromocytoma.
Authors: Shirley A Yao, Elizabeth A Wiley, Lisa R. Susswein, Megan L. Marshall, Natalie J. Carter, Anna K. McGill, Rachel T. Klein, Ying Wang, Kathleen S. Hruska
Journal: Journal of Clinical Oncology (2018)

668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.
CONGENITAL HEART DISEASE CONFERS SUBSTANTIAL RISK OF ACQUIRED CARDIOVASCULAR DISEASE AMONGST BRITISH ADULTS
Authors: Priyanka Saha, Praneetha Potiny, Catherine Tcheandjieu, Susan M. Fernandes, Anitra Romfh, Daniel Bernstein, George K. Lui, Erik Ingelsson, James Priest
Journal: Journal of the American College of Cardiology (2018)