tbuckley/cabot-search huggingface dataset:
Physiological Stress Elicits Impaired Left Ventricular Function in Preterm-Born Adults
Authors: Odaro J. Huckstep, Wilby Williamson, Fernando Telles, Holger Burchert, Mariane Bertagnolli, Charlotte Herdman, Linda Arnold, Robert Smillie, Afifah Mohamed, Henry Boardman, Kenny McCormick, Stefan Neubauer, Paul Leeson, Adam J. Lewandowski
Journal: Journal of the American College of Cardiology (2018)

Experimental and clinical studies show that prematurity leads to altered left ventricular (LV) structure and function with preserved resting LV ejection fraction (EF). Large-scale epidemiological data now links prematurity to increased early heart failure risk. Echocardiography imaging was performed at prescribed exercise intensities to determine whether preterm-born adults have impaired LV functional response to physical exercise. A total of 101 normotensive young adults born preterm (n = 47; mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were recruited for detailed cardiovascular phenotyping. Full clinical resting and exercise stress echocardiograms were performed, with apical 4-chamber views collected while exercising at 40%, 60%, and 80% of peak exercise capacity, determined by maximal cardiopulmonary exercise testing. Preterm-born individuals had greater LV mass (p = 0.015) with lower peak systolic longitudinal strain (p = 0.038) and similar EF to term-born control subjects at rest (p = 0.62). However, by 60% exercise intensity, EF was 6.7% lower in preterm subjects (71.9 ± 8.7% vs 78.6 ± 5.4%; p = 0.004) and further declined to 7.3% below the term-born group at 80% exercise intensity (69.8 ± 6.4% vs 77.1 ± 6.3%; p = 0.004). Submaximal cardiac output reserve was 56% lower in preterm-born subjects versus term-born control subjects at 40% of peak exercise capacity (729 ± 1,162 ml/min/m2 vs. 1,669 ± 937 ml/min/m2; p = 0.021). LV length and resting peak systolic longitudinal strain predicted EF increase from rest to 60% exercise intensity in the preterm group (r = 0.68, p = 0.009 and r = 0.56, p = 0.031, respectively). Preterm-born young adults had impaired LV response to physiological stress when subjected to physical exercise, which suggested a reduced myocardial functional reserve that might help explain their increased risk of early heart failure. (Young Adult Cardiovascular Health sTudy [YACHT]; NCT02103231)
Bax inhibitor‐1 protects from nonalcoholic steatohepatitis by limiting inositol‐requiring enzyme 1 alpha signaling in mice
Authors: Cynthia Lebeaupin, Déborah Vallée, Déborah Rousseau, Stéphanie Patouraux, Stéphanie Bonnafous, Gilbert Adam, Frederic Luciano, Carmelo Luci, Rodolphe Anty, Antonio Iannelli, Sandrine Marchetti, Guido Kroemer, Sandra Lacas‐Gervais, Albert Tran, Philippe Gual, Béatrice Bailly‐Maitre
Journal: Hepatology (2018)

Endoplasmic reticulum (ER) stress is activated in nonalcoholic fatty liver disease (NAFLD), raising the possibility that ER stress‐dependent metabolic dysfunction, inflammation, and cell death underlie the transition from steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH). B‐cell lymphoma 2 (BCL2)‐associated X protein (Bax) inhibitor‐1 (BI‐1), a negative regulator of the ER stress sensor, inositol‐requiring enzyme 1 alpha (IRE1α), has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI‐1 would render the liver vulnerable to NASH because of unrestrained IRE1α signaling. ER stress was induced in wild‐type and BI‐1 –/– mice acutely by tunicamycin (TM) injection (1 mg/kg) or chronically by high‐fat diet (HFD) feeding to determine NAFLD phenotype. Livers of TM‐treated BI‐1 –/– mice showed IRE1α‐dependent NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, hepatocyte death, fibrosis, and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI‐1 down‐regulation parallel to the up‐regulation of IRE1α endoribonuclease (RNase) signaling. In HFD‐fed BI‐1 –/– mice that presented NASH and type 2 diabetes, exaggerated hepatic IRE1α, X‐box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP) expression was linked to activated NLRP3 inflammasome and caspase‐1/‐11. Rises in interleukin (IL)‐1β, IL‐6, monocyte chemoattractant protein 1 (MCP1), chemokine (C‐X‐C motif) ligand 1 (CXCL1), and alanine transaminase (ALT)/aspartate transaminase (AST) levels revealed significant inflammation and injury, respectively. Pharmacological inhibition of IRE1α RNase activity with the small molecules, STF‐083010 or 4μ8c, was evaluated in HFD‐induced NAFLD. In BI‐1 –/– mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte‐specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF‐083010 or 4μ8c. Conclusion: Targeting IRE1α‐dependent NLRP3 inflammasome signaling with pharmacological agents or by BI‐1 may represent a tangible therapeutic strategy for NASH. (H epatology 2018).
Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis
Authors: Jae-Ho Cheong, Han-Kwang Yang, Hyunki Kim, Woo Ho Kim, Young-Woo Kim, Myeong-Cherl Kook, Young-Kyu Park, Hyung-Ho Kim, Hye Seung Lee, Kyung Hee Lee, Mi Jin Gu, Ha Yan Kim, Jinae Lee, Seung Ho Choi, Soonwon Hong, Jong Won Kim, Yoon Young Choi, Woo Jin Hyung, Eunji Jang, Hyeseon Kim, Yong-Min Huh, Sung Hoon Noh
Journal: The Lancet Oncology (2018)
Research is needed to understand the causes of male infertility and develop treatments
Authors: Ingrid Torjesen
Journal: BMJ (2018)

One in six couples in the UK have difficulty conceiving and in at least half of cases the fertility of the man may be responsible, but lack of knowledge about male fertility and how to treat it means that boosting a couple’s pregnancy chances will usually involve a costly invasive intervention for the female partner.

Sarah Martins da Silva, clinical lecturer in reproductive medicine at the University of Dundee, told a press conference on male fertility held in London on 6 March that limited understanding of the sperm function required for fertility meant that the problem of male infertility “is incompletely understood,” so “incredibly” there …
JUNCTIONAL ECTOPIC RHYTHM AFTER ATRIOVENTRICULAR NODAL REENTRANT TACHYCARDIA ABLATION: AN UNDER-RECOGNIZED COMPLICATION
Authors: Nathan Scott Kusterer, Gustavo Morales, Muhammad Butt, Yousef Darrat, Kevin Parrott, Gbolahan Ogunbayo, Katrina Bidwell, Ripa Patel, Brian Delisle, Melissa Czarapata, Samy Elayi
Journal: Journal of the American College of Cardiology (2018)
The summer of smoke: ecosocial and health impacts of a record wildfire season in the Northwest Territories, Canada
Authors: Warren Dodd, Courtney Howard, Caren Rose, Craig Scott, Patrick Scott, Ashlee Cunsolo, James Orbinski
Journal: The Lancet Global Health (2018)

BackgroundBetween June and August 2014, Canada's Northwest Territories experienced their worst wildfire season on record, with prolonged smoke events and poor air quality. In total, 385 separate fires burned 3 400 000 hectares of land costing CAN$56·1 million in firefighting expenses. In the context of climate change, this study sought to explore the lived experience of the 2014 wildfire season among four communities in the Northwest Territories.MethodsQuantitatively, we explored associations between air quality (PM 2.5 level), emergency room admissions for respiratory and cardiac events, and dispensations of salbutamol (non-prescription inhaler) during the summer of 2014 compared to 2012 and 2013. Qualitatively, we conducted 30 semi-structured interviews in four communities (Yellowknife, N’Dilo, Dettah, and Kakisa). Interviews were video recorded, and the audio portion of each interview was transcribed to facilitate analysis and theme generation.FindingsBetween June 15 and August 31, 2014, 55% of days had a PM 2·5 above 25 μg/m3, compared to 4% of days in 2012 and 9% of days in 2013. The highest daily PM 2.5 in 2014 was 320·4 μg/m3. Emergency room visits for asthma and pneumonia increased in 2014 compared to 2012 and 2013, but the number of cardiac-related visits did not change. Primary care visits for cough, asthma, and pneumonia and dispensations for prescription inhalers (salbutamol) also increased in 2014 relative to 2012 and 2013. Interviewees reported how their experiences of evacuation and isolation and feelings of fear, stress, and uncertainty contributed to acute and long-term negative effects on their mental and emotional wellbeing. Prolonged smoke events were linked to extended time indoors and respiratory problems. Livelihood and land-based activities were disrupted for some Indigenous interviewees, which had negative consequences for mental, emotional, and physical wellbeing. Individual and community stories of adaptation and resilience before and during the summer were shared; however, there was consensus about the need for improved risk communication and coordination at the community and territorial level to address similar events in the future.InterpretationCoordinated community-based education, communication, and adaptation initiatives that are inclusive of local knowledge, values, and context are needed to address the expressed needs of community members associated with prolonged smoke events and wildfire seasons.FundingHealth Canada.
Abstract BS1-2: Myeloid-derived suppressor cells: many facets of regulation of tumor progression
Authors: DI Gabrilovich
Journal: Cancer Research (2018)

Abstract Tumor associated macrophages (TAM), myeloid derived suppressor cells (MDSC), represented by PMN-MDSC and M-MDSC, and dendritic cells (DC) are major components of tumor microenvironment playing critical role in tumor progression. There are now compelling evidence linking MDSC with negative clinical outcomes in many types of cancer. Therefore, these cells are attractive therapeutic targets. Recently, several therapeutic strategies have been developed that target MDSC in mouse animal models and in first clinical trials. Recent findings of selective targeting of MDSC in cancer patients using agonistic TRAIL receptor DR5 antibody will be discussed. In 16 patients with advanced solid tumors this antibody demonstrated selective depletion of MDSC without affecting populations of neutrophils, monocytes, or lymphocytes. Another therapeutic strategy involves histone deacetilase inhibitor – entinostat. Recent study in tumor-bearing mice revealed that entinostat slightly increased expansion and accumulation of granulocytic cells in tumors. However, in contrast to untreated mice, these cells lacked suppressive activity. This effect was associated with potent antitumor activity of combination of entinostat with check-point inhibitors. By studying the effect of CSF1R inhibitor in tumor-bearing mice we identified the complex network regulating different groups of myeloid cells in tumor microenvironment. This network involves tumor cells and cancer associated fibroblast and protect tumors from loss of individual component of myeloid cell compartment. We determined that this network is operational not only in mice but also in cancer patients. Targeting of this network dramatically enhance the effect of cancer therapy. Citation Format: Gabrilovich DI. Myeloid-derived suppressor cells: many facets of regulation of tumor progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS1-2.
P077 Effects of il-17 and the hepatocyte–mononuclear cell interactions in the hepatic inflammatory response
Authors: A Beringer, ND Thiam, J Molle, B Bartosch, P Miossec
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Interleukin-17A (IL-17), tumour necrosis factor-α (TNFα) and IL-6 are pro-inflammatory cytokines involved in many autoimmune and inflammatory diseases including rheumatoid arthritis. Because most acute-phase proteins are produced by the liver, the hepatic response plays an important role in systemic inflammation. By producing chemokines such as CCL-20 that attract Th17 cells, hepatocytes can recruit mononuclear cells in liver, which leads to chronic hepatitis. <h3>Objectives</h3> To determine the effect of the IL-17/TNFα combination and the contribution of hepatocyte–peripheral blood mononuclear cell (PBMC) interactions in the hepatic inflammatory response. <h3>Methods</h3> Human HepaRG cell line and primary human hepatocytes (PHH) were cultured with or without IL-6, anti-IL-6 receptor (anti-IL-6R) antibody, IL-17 and/or TNFα. For co-cultures, PBMC from healthy donors activated or not with phytohemagglutinin (PHA) were added on hepatocytes at a 5:1 ratio. Transwell system was used to study the contribution of the direct cell-cell contact. Cytokine expression and production were quantified by qRT-PCR and ELISA respectively and the secretion of C-reactive protein (CRP) by an automated analyzer. <h3>Results</h3> IL-17 and TNFα induced in synergy the hepatic IL-6 production (&gt;8 fold, p&lt;0.01) and CCL-20 expression (&gt;100 fold, p&lt;0.01). CRP secretion was induced by IL-17/TNFα and the anti-IL-6R inhibited this induction. CCL-20 expression was not increased by IL-6 stimulation or reduced by the addition of the anti-IL-6R to the IL-17/TNFα treatment. In HepaRG cell-PBMC cultures, IL-6 and IL-17 were produced only in PHA-activated conditions and the IL-6 and IL-17 levels were higher in co-cultures vs PBMC monocultures (&gt;14 and &gt;2 fold respectively, p&lt;0.01). Transwell system that avoids direct cell-cell contact decreased the IL-6 and IL-17 secretion by 4- and 2-fold respectively in PHA-activated HepaRG cell-PBMC cultures. CRP production increased when PHH were cultured in presence of PHA-activated PBMC compared to PHH alone with PHA. <h3>Conclusions</h3> The IL-17/TNFα synergistic effect on hepatocytes mediates systemic inflammation by inducing CRP secretion through the IL-6 pathway and mononuclear cell recruitment by acting on CCL-20 expression in an IL-6 independent manner. Direct and indirect hepatocyte-PBMC interactions contribute to the hepatic inflammatory response by increasing the IL-6 and IL-17 secretion. The induction of Th17 cell differentiation by IL-6 and the increase of CCL-20 mediated Th17 cell recruitment by IL-17 may lead to a vicious and chronic inflammatory cycle. <h3>Disclosure of interest</h3> None declared
Widespread somatic loss of heterozygosity as a possible marker of disease aggressiveness in metastatic well differentiated pancreatic neuroendocrine tumors.
Authors: Omobolaji Oyekunle Akala, Ronak Shah, Brian R. Untch, Virginia Kelly, Joanne F. Chou, Marc Ladanyi, Michael F. Berger, David S. Klimstra, Diane Lauren Reidy, Nitya Prabhakar Raj
Journal: Journal of Clinical Oncology (2018)

275 Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value &lt; 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p &lt; 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p &lt; 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.
Yorkshire microsurgery workshop
Authors: Laurence Glancz
Journal: BMJ (2012)

The Yorkshire microsurgery workshop is an affordable, hands-on introduction to the principles of performing microsurgery, held in the skills laboratory at Pinderfields General Hospital in Wakefield. 

This course is aimed at core surgical and plastic surgery trainees with little or no previous experience in microsurgery, but it could also serve as a refresher course for more senior trainees in plastic or hand surgery. The 11 delegates on my course comprised a fairly even spread of year 1 core trainees (CT1s) to year 4 specialty trainees (ST4s), with an ST7 the most senior participant.

I did this course as a CT1 before starting my six month CT2 rotation in plastic surgery, to give me the basic microsurgical skills and knowledge. The aim was to get hands-on experience in a safe and well supervised environment. 

This was the first time that the course had been run, although the same convenors have held the successful MY plastic surgery course on several occasions.1 These courses, along with the other courses run by the …
Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus–Infected Donors to Noninfected Recipients
Authors: Christine M. Durand, Mary G. Bowring, Diane M. Brown, Michael A. Chattergoon, Guido Massaccesi, Nichole Bair, Russell Wesson, Ashraf Reyad, Fizza F. Naqvi, Darin Ostrander, Jeremy Sugarman, Dorry L. Segev, Mark Sulkowski, Niraj M. Desai
Journal: Annals of Internal Medicine (2018)

Background: Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective: To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non–HCV-infected recipients (that is, HCV D+/R− transplantation). Design: Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649) Setting: Single center. Participants: 10 HCV D+/R− kidney transplant candidates older than 50 years with no available living donors. Intervention: Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR–EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR–EBR for 12 weeks of triple therapy. Measurements: The primary safety outcome was the incidence of adverse events related to GZR–EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results: Among 10 HCV D+/R− transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation: Nonrandomized study design and a small number of patients. Conclusion: Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R– kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source: Merck Sharp & Dohme.
Doctors must work with finance staff to tackle workforce and funding challenges
Authors: Matthew Limb
Journal: BMJ (2015)

Doctors and finance professionals must strike a better understanding to tackle the NHS’s major workforce and financial challenges, the president of the Healthcare Financial Management Association has said.

Sue Lorimer acknowledged that “mistrust” had tarnished relations between the two professional groups. “I think that does exist to some degree,” she told BMJ Careers. “We’ve not engaged with doctors as much as we should have. We need to understand much more . . . what drives them, so that they can understand what drives us.”

Lorimer, who is also business director for the NHS Trust Development Authority, said that there were many and growing examples of successful engagement between doctors and finance staff. “The only way we’re going to get out of the financial difficulties we have currently is working closely with doctors,” she said.

In an interview with BMJ Careers she spoke about the challenges for the relationship, given that NHS trusts were facing a potential £2bn deficit next year, which she said was “not sustainable.”

The King’s Fund reported last month that 96% of acute care NHS trusts and more than 50% …
Spinal Dysraphism Presenting as a Translucent Papule in a Man
Authors: Justin J. Finch, Chase W. Kwon, Hanspaul S. Makkar
Journal: JAMA Dermatology (2018)

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Uncomplicated 90Y Selective Internal Radio Therapy in a Patient With Hepatocellular Carcinoma After Arterial and Portal Vein Embolizations
Authors: Jochem van der Pol, Judith de Vos-Geelen, Jan Bucerius, Cristina Mitea, Christiaan van der Leij
Journal: Clinical Nuclear Medicine (2018)

Selective internal radio therapy (SIRT) with Y-glass microspheres was performed in a cirrhotic patient with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage C) after arterial coil embolization for treatment of intratumoral hemorrhage and planned preoperative right portal vein embolization. Three technetium Tc macro-albumin-aggregate injections were needed to optimize intralesional uptake without extrahepatic deposition. The consecutive SIRT treatment was uncomplicated with a remarkable result.