tbuckley/cabot-search huggingface dataset:
Maternal Plasma per- and Polyfluoroalkyl Substance Concentrations in Early Pregnancy and Maternal and Neonatal Thyroid Function in a Prospective Birth Cohort: Project Viva (USA)
Authors: Emma V. Preston, Thomas F. Webster, Emily Oken, Birgit Claus Henn, Michael D. McClean, Sheryl L. Rifas-Shiman, Elizabeth N. Pearce, Lewis E. Braverman, Antonia M. Calafat, Xiaoyun Ye, Sharon K. Sagiv
Journal: Environmental Health Perspectives (2018)

Background: Prenatal exposure to some per- and polyfluoroalkyl substances (PFASs) may disrupt maternal and neonatal thyroid function, which is critical for normal growth and neurodevelopment. Objectives: We examined associations of PFAS exposure during early pregnancy with maternal and neonatal thyroid hormone levels. Methods: We studied 732 mothers and 480 neonates in Project Viva, a longitudinal prebirth cohort in Boston, Massachusetts. We quantified six PFASs, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and maternal thyroid hormones [thyroxine (T4), Free T4 Index (FT4I), thyroid stimulating hormone (TSH)] in plasma samples collected at a median 9.6 wk gestation and neonatal T4 levels from postpartum heel sticks. We estimated associations of PFAS concentrations with thyroid hormone levels using covariate-adjusted linear regression models and explored effect measure modification by maternal thyroid peroxidase antibody (TPOAb) status and infant sex. Results: PFAS concentrations were not associated with maternal T4, but PFOA, perfluorohexane sulfonate (PFHxS), and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) were inversely associated with maternal FT4I [e.g., −1.87% (95% confidence interval (CI): −3.40, −0.31) per interquartile (IQR) increase in PFOA]. PFAS concentrations [PFOA, PFOS, and perfluorononanoate (PFNA)] were inversely associated with TSH levels in TPOAb-positive women only. Prenatal PFOS, PFOA, and PFHxS concentrations were inversely associated with T4 levels in male [e.g., PFHxS, quartile 4 vs.1: −2.51μg/dL (95% CI: −3.99, −1.04 )], but not female neonates [0.40μg/dL (95% CI: −0.98, 1.79)]. Conclusions: In this study, prenatal exposure to some PFASs during early pregnancy was inversely associated with maternal FT4I and neonatal T4 in male infants. These results support the hypothesis that prenatal exposure to PFASs influences thyroid function in both mothers and infants. https://doi.org/10.1289/EHP2534
IMPACT OF MODERATE/SEVERE TRICUSPID REGURGITATION ON SURVIVAL OF PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Maria Drakopoulou, Konstantinos Toutouzas, Konstantinos Stathogiannis, George Latsios, Andreas Synetos, George Oikonomou, Vasiliki Penesopoulou, Maria Xanthopoulou, George Trantalis, Odysseas Kaitozis, Eleftherios Tsiamis, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
P005 Influence of macrophage polarisation on expression of peptidylarginine deiminases 2 and 4 that catalyse citrullination of the proteins targeted by anti-citrullinated protein/peptide autoantibodies (ACPA)
Authors: M-C Méchin, G Serre, C Clavel
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Autoantibodies to citrullinated proteins (ACPA) are specifically associated to rheumatoid arthritis (RA) and probably involved in its pathophysiology. ACPA are produced in the inflamed synovial tissue (ST). We demonstrated that peptidylarginine deiminases (PAD) 2 and 4 are present in the tissue and probably responsible for fibrin citrullination, and consequently for genesis of the epitopes targeted by ACPA. PAD2 and 4 are expressed in the intima and the subintimal inflammatory infiltrates, essentially by CD68 +mononuclear cells.<sup>1</sup> We suspected macrophages (MΦ) of the ST to be responsible for synthesis and release of PADs in the interstitium, inducing citrullination of the local fibrin deposits. We generated <i>in vitro</i> various subsets of MΦ in the presence of IFN-γ, IL-4, IL-10 or M-CSF, and observed a major influence of the phenotype of polarised MΦ on cytokine response to ACPA-containing immune complexes.<sup>2</sup> <h3>Objectives</h3> The aim of the current study was to evaluate expression of PAD2 and 4 by various subsets of polarised MΦ. <h3>Methods</h3> CD14-positive monocytes from healthy donors were cultured in presence of M-CSF, IFN-γ, IL-4 or IL-10. The expression of the <i>PADI</i>2 and 4 genes was measured by RT-qPCR and the expression of PAD2 and 4, evaluated by immunoblotting of total cell extracts. <h3>Results</h3> <i>PADI</i>2 and 4 mRNAs are expressed in monocytes while PAD2 and 4 proteins are also immunodetected in these cells. In the different MΦ subsets, <i>PADI</i>2 mRNAs are less detected than in the related monocytes except for the IFN-γ MΦ subset where it is detected at a higher relative rate. By contrast, <i>PADI</i>4 gene expression is suppressed in all MΦ subsets except the IFN-γ MΦ where <i>PADI</i>4 mRNAs are weakly detected. Consistently with mRNA analysis, PAD2 is detected in all polarised MΦ and more strongly expressed in IFN-γ MΦ whereas PAD4 is no longer detectable except faintly for the IFN-γ MΦ. <h3>Conclusions</h3> This study shows that PAD2 is expressed at various degrees in the four analysed MΦ phenotypes but PAD4, only in the IFN-γ MΦ, both enzymes being expressed in monocytes. This reinforces the hypothesis of a role for monocytes and MΦ in genesis of ACPA epitopes in the ST. <h3>References</h3> . Foulquier, et al. Arthritis Rheum2007. . Clavel, et al. Ann Rheum Dis2016. <h3>Acknowledgements</h3> The technical assistance of Céline Thomann, Géraldine Offer and Imène Belhaouane is gratefully acknowledged. <h3>Disclosure of interest</h3> None declared
Trust must pay £4.4m for failure to warn about risks of spinal surgery
Authors: Clare Dyer
Journal: BMJ (2018)

An NHS trust will have to pay £4.4m (€5m; $6.1m) in damages to a patient left permanently disabled by a spinal disc operation because the surgeon failed to explain the risk of spinal cord damage, even though he performed the operation competently.

A High Court judge has ruled that the patient would not have gone ahead with the operation if the risks had been properly explained and therefore that Hillingdon Hospitals NHS Foundation Trust must compensate her.1

Tracy Hassell was a 41 year old mother of three and head of year at …
The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells
Authors: Penkhae Utaijaratrasmi, Kulthida Vaeteewoottacharn, Takaaki Tsunematsu, Pranisa Jamjantra, Sopit Wongkham, Chawalit Pairojkul, Narong Khuntikeo, Naozumi Ishimaru, Yongyut Sirivatanauksorn, Ananya Pongpaibul, Peti Thuwajit, Chanitra Thuwajit, Yasusei Kudo
Journal: Molecular Cancer (2018)

Cholangiocarcinoma (CCA) has an abundance of tumor stroma which plays an important role in cancer progression via tumor-promoting signals. This study aims to explore the microRNA (miRNA) profile of CCA-associated fibroblasts (CCFs) and the roles of any identified miRNAs in CCA progression.miRNA expression profiles of CCFs and normal skin fibroblasts were compared by microarray. Identified downregulated miRNAs and their target genes were confirmed by real-time PCR. Their binding was confirmed by a luciferase reporter assay. The effects of conditioned-media (CM) of miRNA mimic- and antagonist-transfected CCFs were tested in CCA migration in wound healing assays. Finally, the levels of miRNA and their target genes were examined by real-time PCR and immunohistochemistry in clinical CCA samples.miR-15a was identified as a downregulated miRNA in CCFs. Moreover, PAI-2 was identified as a novel target gene of miR-15a. Recombinant PAI-2 promoted migration of CCA cells. Moreover, CM from miR-15a mimic-transfected CCFs suppressed migration of CCA cells. Lower expression of miR-15a and higher expression of PAI-2 were observed in human CCA samples compared with normal liver tissues. Importantly, PAI-2 expression correlated with poor prognosis in CCA patients.These findings highlight the miR-15a/PAI-2 axis as a potential therapeutic target in CCA patients.
Multispecific antibodies targeting CD38 show potent tumor-specific cytotoxicity.
Authors: Shelley Force Aldred, Andrew Boudreau, Ben Buelow, Starlynn Clarke, Kevin Dang, Laura Davison, Katherine Harris, Suhasini Iyer, Brett Jorgensen, Heather Ogana, Duy Pham, Payal Pratap, Udaya Rangaswamy, Ute Schellenberger, Nathan Trinklein, Harshad Ugamraj, Omid Vafa, Wim Van Schooten
Journal: Journal of Clinical Oncology (2018)

57 Background: Multivalent antibodies targeting either CD38 alone or CD38 in conjunction with PD-L1 may yield therapeutics with superior biological activities and provide benefit for treating malignancies expressing low levels of CD38 (MCL, NHL, T cell lymphomas and Daratumumab refractory MM). Multivalent, multispecific antibodies kill CD38 low cells through a variety of mechanisms including stronger and more specific engagement of CD38. Potent and directed immune checkpoint inhibition is realized by adding an anti-PD-L1 binding domain. Teneobio’s discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Methods: Individual UniDabs targeting CD38 and PDL1 were identified using our unique sequence-based discovery platform and high-throughput lead evaluation pipeline (TeneoSeek). This robust screening workflow enables evaluation of a large diversity of natural fully human antibodies, targeting multiple epitopes on a single antigen and uncovering important sequence activity relationships. UniDabs from transgenic rats are ideal building blocks for the generation of potent and highly manufacturable multivalent antibody therapeutics. Results: We have identified UniDabs that efficiently block PD-1/PD-L1 interaction as well as additional UniDabs that bind to five different functional epitopes on human CD38. Using different combinations and arrangements of UniDabs, a variety of multivalent antibodies were constructed and evaluated in in vitro models. Specific combinations of UniDabs show more potent cytotoxic effects than Daratumumab for multiple mechanisms including CDC and direct apoptosis. Conclusions: Data from a range of assay types show that multivalent UniAbs targeting CD38 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action.
Reducing Harms in Lung Cancer Screening—Bach to the Future
Authors: Michael Incze, Rita F. Redberg
Journal: JAMA Internal Medicine (2018)

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Do I need a homeland medical registration number to get a job in Australia or New Zealand?
Authors: Miriam Martin
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
A NEW PERCUTANEOUS TECHNIQUE FOR EFFECTIVE VASCULAR ACCESS SITE CLOSURE IN PATIENTS UNDERGOING TRANSFEMORAL AORTIC VALVE IMPLANTATION (TAVI) AND THORACO-ABDOMINAL AORTIC ANEURYSM REPAIR (TAAR)
Authors: Gurbhej Singh, Sorropago Giovanni, Andrea Demarchi, Gioacchino Valenti, Antonio Sorropago, Valerio Stefano Tolva, Filippo Scalise
Journal: Journal of the American College of Cardiology (2018)
RORγ agonist LYC-55716, a novel small molecule immunotherapy: Rationale for clinical evaluation in non-small cell lung cancer based on translational and bioinformatic evaluation.
Authors: Laura Carter, Xikui Liu, Hongxiu Li, Elizabeth Zawidzka, Yilin Gao, Brian Fox, Garry Weems, H. Jeffrey Wilkins, Xiao Hu
Journal: Journal of Clinical Oncology (2018)

171 Background: Retinoic acid receptor–related orphan receptor γ (RORγ) agonists modulate immune cell gene expression to enhance effector function and decrease regulatory T cell formation and expression of checkpoint pathways. RORγ agonists have demonstrated antitumor activity in syngeneic tumor models. Translational and bioinformatic assessments were conducted to support inclusion of patients with non–small-cell lung cancer (NSCLC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: The Cancer Genome Atlas (TCGA) NSCLC dataset was evaluated for (a) expression of RORγ and RORγ-inducing cytokines and correlation with survival; (b) genes related to RORγ biology, biomarkers of endogenous RORγ agonists; and (c) tumor microenvironment (TME) immune profiles. RORγ expression and the in vitro effects of a RORγ agonist on peripheral blood mononuclear cells (PBMCs) from lung adenocarcinoma (LA) and squamous cell carcinoma (SCC) patients were assessed. Results: In TCGA, 25% of NSCLC tumors expressed moderate/high levels of RORγ, suggesting infiltration of Type 17 cells. There was a statistically significant correlation between high RORγ expression and improved survival in LA patients. Genes that support Type 17 cell formation (IL1B, IL23A, IL6) were expressed in ~50% of tumors. RORγ expression was confirmed in PBMCs isolated from LA and SCC patients. Analysis of TCGA data and patient samples identified low expression of sterol efflux and uptake genes, suggesting low levels of endogenous RORγ agonist in TME. In TCGA, high mutational burden and high expression of immune-related genes were found in NSCLC tumors. RORγ agonist treatment of PBMCs from LA and SCC patients increased IL-17A and IL-26 (LA and SCC) and decreased PD1 (LA). In Phase 1 clinical testing, LYC-55716 has been well tolerated, demonstrating long-term disease stabilization in heavily pretreated patients. Conclusions: Bioinformatic analyses of RORγ expression/biology, correlation with improved survival, plus in vitro findings support inclusion of NSCLC in an ongoing Phase 2 clinical trial of LYC-55716.
GMC has investigated 22 trainees over recreational drug use since 2011
Authors: Abi Rimmer
Journal: BMJ (2015)

Twenty two junior doctors were investigated by the General Medical Council between 2011 and 2015 over recreational drug use, figures released by the regulator have shown.

From January 2011 to January 2015 the GMC investigated 22 doctors who were less than five years after qualification for alleged recreational drug use. The cases were categorised by the GMC as controlled substances offences, driving under the influence of drugs, mental and behavioural illness (substance misuse), or risks imposed by health (substance misuse). The GMC released the data in response to a request made under …
Efficacy and safety of continuous every-2-week dosing of ixekizumab over 52 weeks in patients with moderate-to-severe plaque psoriasis in a randomized phase III trial (IXORA-P)
Authors: R.G. Langley, K. Papp, M. Gooderham, L. Zhang, C. Mallinckrodt, N. Agada, A. Blauvelt, P. Foley, P. Polzer
Journal: British Journal of Dermatology (2018)

Ixekizumab is an interleukin‐17A antagonist approved for treatment of moderate‐to‐severe plaque psoriasis with a recommended 160‐mg starting dose, then 80 mg every 2 weeks (Q2W) to week 12, and every 4 weeks (Q4W) thereafter. To evaluate continuous Q2W dosing over 52 weeks. In this phase III, multicentre, double‐blinded, parallel‐group trial, three ixekizumab dosing regimens were assessed for efficacy and safety at week 52 in patients with moderate‐to‐severe plaque psoriasis randomized at a 2 : 1 : 1 ratio to continuous Q2W (n = 611), continuous Q4W (n = 310) or dose adjustment per protocol (Q4W/Q2W, n = 306), each with a 160‐mg starting dose. Dose adjustment was determined by predefined criteria to which investigators were blinded; 72 (23?5%) patients in the Q4W/Q2W group adjusted dose. Efficacy outcomes were evaluated using logistic regression. Co‐primary end points were met at week 52: Psoriasis Area and Severity Index 75 responses for Q2W and Q4W dose groups were 85·9% and 79·0%, respectively (P = 0·006), and static patient global assessment 0/1 responses for Q2W and Q4W dose groups were 78·6% and 70·6%, respectively (P = 0·005). Treatment‐emergent and serious adverse events were comparable across dose groups. Ixekizumab Q2W had higher efficacy at week 52 than ixekizumab Q4W, with no increase in safety events.
Abstract 12286: Electrical Muscle Stimulation Improves Neurovascular Control and Exercise Tolerance in Hospitalised Advanced Heart Failure Patients
Authors: Raphaela V Groehs, Ligia M Antunes-Correa, Thais S Nobre, Maria-Janieire N Alves, Maria Urbana P Rondon, Antônio Carlos Pereira-Barretto, Carlos E Negrao
Journal: Circulation (2015)

Introduction: Advanced heart failure (HF) patients may stay for a long period of time in the hospital for the treatment of HF and prolonged inactivity causes complications that result in worsening of exercise tolerance. On the other hand, there is evidence that treatment with muscle low-frequency electrical stimulation (FES) provides important benefits for HF patients. This study investigated the effects of FES on neurovascular control and exercise tolerance in HF hospitalized patients. Methods and results: Thirty hospitalized patients for treatment of decompensated HF, functional class IV NYHA and ejection fraction ≤ 30% were consecutively randomised into two groups: 1) FES(n= 15; 54±2 years) and control(n= 15; 49±2 years). Muscle sympathetic nerve activity (MSNA) was directly recorded via microneurography and blood flow by venous occlusion plethysmography. Heart rate and blood pressure were evaluated on a beat-to-beat basis (Finometer). Exercise tolerance by six-minute walk test, quadriceps muscle strength by a dynamometer and quality of life by Minnesota Questionnaire. FES consisted of stimulating the lower limbs at 10 Hz frequency, 150 ms pulse width and 70 mA intensity for 60 min/day for 7 days/week for 10 consecutive days. The control group underwent electrical stimulation at intensity of 20 mA. Baseline characteristics were similar between groups, except age that was higher in FES group. FES significantly decreased MSNA burst frequency (49 ±5 vs. 35±5, P= 0.002) and burst incidence (61 ±6 vs. 49±7, P= 0.04). In addition, FES significantly increased leg blood flow (0.88 ±0.09 vs. 1.47 ±0.14, P&lt;0.001) and muscle strength (13 ±1 to 21 ±2, P&lt;0.001). No changes were found in control group. Walking distance (304 ±25 to 436 ±26, P&lt;0.001 vs. 320 ±22 to 358 ±22, P= 0.001) and quality of life (69 ±5 to 26 ±3, P&lt;0.001 vs. 70 ±3 to 45 ±3, P&lt;0.001) improved in FES and control groups, respectively. However, these changes were greater in FES group. Conclusion: FES improves MSNA and vasoconstriction and increases exercise tolerance, muscle strength and quality of life in hospitalised HF patients. These findings support the use of FES as an adjuvant therapy for patients hospitalised to achieve the stabilisation of HF.
Initial agreement is reached on EU rules on professional mobility
Authors: Helen Jaques
Journal: BMJ (2013)

EU institutions have hammered out an initial agreement on a directive that would make it easier for EU doctors to practise in other European countries.

Full details of the directive on the mutual recognition of professional qualifications are not yet available, but the deal is understood to cover all the substantive proposals set out in the draft directive in December 2011.12

The draft directive agreed by the European parliament, the Council of Ministers (representing the member states), and the European Commission will allow the UK General Medical Council to …
The validity of repeat prostate biopsy in prior biopsy negative patients: MRI-TRUS fusion guided biopsy.
Authors: Jinho Hwang, Jung Jun Kim, Jong Jin Oh, Chang Wook Jeong, Sangchul Lee, Sung Kyu Hong
Journal: Journal of Clinical Oncology (2018)

95 Background: To investigate validity of magnetic resonance imaging (MRI)-transrectal ultrasound fusion target biopsy (Fusion-Bx) compared with transrectal ultrasound-guided biopsy (TRUS-Bx) by evaluating detection rate of prostate cancer (PCa). Methods: Medical records of 376 patients with prior negative TRUS-Bx who underwent repeat prostate biopsy between Aug. 2015 and Apr. 2017 were retrospectively reviewed. The cohort was stratified into two groups (TRUS-Bx and Fusion-Bx) and clinical and biopsy characteristics patterns were analyzed. Conventional systemic randomized 12-core biopsy was performed in TRUS-Bx group whereas Fusion-Bx group applied additional 2-croes of target biopsy against suspicious lesions in MRI. Results: There were total 195 and 181 patients in TRUS-Bx and Fusion-Bx group, respectively. The overall cancer detection rate was slightly higher in Fusion-Bx group, but no statistical significance was observed (24.6% vs 28.7%, p = 0.367). Fusion-Bx group showed a significantly greater detection rate in target core analysis (5.0% vs 17.7%, p = 0.044). In confirmed positive biopsy patients, Fusion-Bx group had a higher rate of clinically significant prostate cancer (CsPCa) cases, but failed to achieve statistical significance (85.4% vs 92.3%, p = 0.271). When the patients with highly or very highly suspicious MRI (maximum image grade 4-5) findings in Fusion-Bx group was compared to the whole cohort of TRUS-Bx group, Fusion-Bx group was significantly greater in terms of overall detection rate (24.6% vs 38.0%, p = 0.017) and CsPCa detection rate (85.4% vs 97.0%, p = 0.009). Higher the target image grade, greater biopsy yield was achieved. Conclusions: For the patients who underwent repeat biopsy due to prior negative results, fusion-Bx showed better clinical significance including detection rate. A further study with a larger cohort size and prospective design is still needed to confirm the validity of Fusion-Bx.
I'm a fresh graduate, have three years' experience as a general practitioner, and have just passed my PLAB1. I'm awaiting my PLAB 2 in November. I want to apply for the foundation scheme programme 2 (year 2005). Please let me know how I can apply for this scheme.
Authors: Rahul Rao
Journal: BMJ (2004)

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