tbuckley/cabot-search huggingface dataset:
Uric acid, lung function and COPD: a causal link is unlikely
Authors: Seif O Shaheen
Journal: Thorax (2018)

> Happy the man who has been able to learn the causes of things—Virgil

In epidemiology we strive to identify the root causes of disease, in the hope that this will enable us to devise preventive strategies. Observational studies constitute our ‘bread and butter’ and, in carrying out such studies, we find associations and make judgements on whether they have arisen through chance, bias or confounding, before considering possible causal interpretations. Confounding is the bane of an epidemiologist’s life because, however hard we try to rule it out as a possible explanation for a link between exposure and disease in observational studies, it is nigh on impossible to do so with total confidence. While we do our best to take potential confounders ‘out of the equation’ in our analyses, usually by controlling for them in multivariable regression models, if confounders have been measured imprecisely there will still be residual confounding, and other confounders may not have been measured (some may be unknown) and therefore cannot be controlled for.

The gold standard study design for obtaining unconfounded evidence of causality is the randomised controlled trial (RCT), because randomisation should lead to even distribution of confounders between treatment arms. However, sometimes trials are not ethical to conduct and, even if feasible, large trials are very expensive and time-consuming. In recent years a welcome addition to the epidemiologist’s armoury for strengthening causal inference in observational studies has been Mendelian randomisation (MR), an approach championed by George Davey Smith and colleagues,1 which can be regarded as a ‘natural RCT’. MR is a form of instrumental variable analysis, whereby a genetic variant can be used as a proxy for a specific exposure to test whether that exposure is likely to …
Multifunctional Cell Instructive Silk‐Bioactive Glass Composite Reinforced Scaffolds Toward Osteoinductive, Proangiogenic, and Resorbable Bone Grafts
Authors: Joseph Christakiran Moses, Samit Kumar Nandi, Biman B. Mandal
Journal: Advanced Healthcare Materials (2018)

Abstract The successful regeneration of large volume bone defects necessitates the use of proangiogenic and resorbable scaffolding matrix. Impaired and slow ingrowth of host vasculature within implanted grafts greatly compromises its effective osseointegration. By addressing this, it is demonstrated that the use of copper doped bioactive glass functionalizes silk microfiber reinforcements to improve the physicochemical and osteoinductive properties of two silk scaffolding matrices (mulberry Bombyx mori and non‐mulberry Antheraea assama ) employed in the study. The reinforced composite matrices increase the surface area and present an open porous biomimetic micromillieu favoring stem cell and endothelial cell migration within the matrix. Biochemical results indicate the stabilization of hypoxia‐inducible factor‐1α and expression of C‐X‐C chemokine receptor type‐4 in adipose derived human mesenchymal stem cells, which regulate the downstream proangiogenic signaling and endothelial cell homing, respectively. Osteoinduction, matrix turnover, and resorption effectiveness are favored better in the non‐mulberry silk matrices. The composite matrices significantly promote neo‐osseous tissue formation in volumetric femur defect in rabbits with periosteal restoration seen in the non‐mulberry silk composite matrices. Evidences of total resorption, enhanced vascular‐fibrous tissue ingrowth within the scaffold, vouch for the potential clinical translation of these developed composite silk matrices.
Kinetics and dosimetric predictors of acute radiation-induced lymphopenia in pancreatic cancer.
Authors: Susannah G. Ellsworth, Todd Mereniuk, Robert F Hobbs, Hong Zhang, Joseph M. Herman, Stuart A. Grossman, Bert H. O'Neil, Safi Shahda, Radhe Mohan, Feng-Ming (Spring) Kong, Jianyue Jin
Journal: Journal of Clinical Oncology (2018)

300 Background: Radiation (RT) induced lymphopenia (RIL) is an adverse prognostic factor in pancreatic cancer (PC) and is likely due to the irradiation of lymphocytes in the RT field. The goal of this study was to identify dosimetric predictors for high rates of absolute lymphocyte count (ALC) loss during RT for PC. Methods: This was a retrospective study of 34 PC patients in an institutional database who had received concurrent 5-FU or gemcitabine-based chemoradiation (50-54 Gy) and had ≥ 3 ALCs measured during RT. Baseline ALC was normal (&gt;1000 cells/uL) in 28/34 (82%) and grade 3-4 RIL occurred in 24/34 (71%). ALC was plotted against fraction # and a best-fit line for each patient was created to determine per-fraction loss in ALC (PFLAC). Linear regression was used to correlate PFLAC with dosimetric parameters including mean dose to gut, liver, kidney, spleen, and cisterna chyli, as well as estimated dose to immune cells (EDIC), which calculates dose to immune cells according to the % of body lymphocytes contained in each organ. Results: All patients exhibited exponential loss in ALC during RT. Mean PFLAC was 6.8% (range 1.7-13.4); fraction # was strongly correlated with ALC (mean R 2 = 0.89). Patients with &gt;/= grade 3 lymphopenia had a significantly higher PFLAC than those with grade 0 - 2 lymphopenia (mean daily loss 7.8% in Gr 3-4 vs. 4.8% in Gr 0-2, p = 0.001; independent sample T test). Field size was not correlated with PFLAC for high (&gt; 1 Gy) or low (&lt; 0.5 Gy) isodose volumes. Mean whole body (r = 0.59, p &lt; 0.001), bowel (r = 0.39, p = 0.012), liver (r = 0.42, p = 0.007), and cisterna chyli (r = 0.583, p = 0.004) doses were moderately correlated with PFLAC; mean kidney (r = 0.22, p = 0.11) and spleen (r = 0.26, p = 0.06) doses were weakly correlated with PFLAC. EDIC was more strongly correlated with PFLAC than any individual organ mean dose (r = 0.69, p &lt; 0.001). Conclusions: Patients undergoing RT for PC experience a predictable RIL characterized by an exponential loss of lymphocytes per day. PFLAC is a useful method of characterizing RIL and facilitates evaluation of dosimetric predictors of RIL. We identified dose to cisterna chyli as a significant contributor to RIL in PC; however, EDIC has a stronger correlation with RIL severity than any single organ dose.
Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies
Authors: Simon Tiberi, Nelita du Plessis, Gerhard Walzl, Michael J Vjecha, Martin Rao, Francine Ntoumi, Sayoki Mfinanga, Nathan Kapata, Peter Mwaba, Timothy D McHugh, Giuseppe Ippolito, Giovanni Battista Migliori, Markus J Maeurer, Alimuddin Zumla
Journal: The Lancet Infectious Diseases (2018)
Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update
Authors: Markus Ketteler, Geoffrey A. Block, Pieter Evenepoel, Masafumi Fukagawa, Charles A. Herzog, Linda McCann, Sharon M. Moe, Rukshana Shroff, Marcello A. Tonelli, Nigel D. Toussaint, Marc G. Vervloet, Mary B. Leonard
Journal: Annals of Internal Medicine (2018)

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis.Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations.The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.
Abstract 17193: Combination of High-sensitivity Troponin I and N-terminal Pro-B-type Natriuretic Peptide Predicts Future Hospital Admission for Heart Failure in High-risk Hypertensive Patients With Preserved Left Ventricular Ejection Fraction
Authors: Ryunosuke Okuyama, Junnichi Ishii, Hiroshi Takahashi, Hidek Kawai, Takashi Takashi, Masahide Harada, Akira Yamada, Sadako Motoyama, Shigeru Matsui, Hiroyuki Naruse, Mutsuharu Hayashi, Masayoshi Sarai, Midori Hasegawa, Eiichi Watanabe, Atsushi Suzuki, Hideo Hideo, Yukio Yuzawa, Yukio Ozaki
Journal: Circulation (2016)

Background:  Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to current hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident HF in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF).   Methods:  Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 hypertensive outpatients (mean age of 68.5 yrs) with LVEF ≥ 50%, no symptomatic HF, and at least one of the following comorbidities: stage 3 or 4 chronic kidney disease, diabetes, and stable coronary artery disease.   Results:  During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved LVEF (HFpEF) and 13 for HF with reduced LVEF (HFrEF; LVEF    Conclusions:  The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.
Public health cuts are blamed for UK’s worsening child health outcomes
Authors: Jacqui Wise
Journal: BMJ (2018)

The UK is falling behind most other high income countries on many key measures of child health, says a major report from the Nuffield Trust and the Royal College of Paediatrics and Child Health.1

After years of progress the UK is now stalling in areas such as infant mortality and immunisation levels and is lagging behind other comparable countries on mortality, breast feeding, and obesity rates.

Ronny Cheung, paediatrician and author of the report, warned, “The recent changes to the UK’s trajectory on life expectancy, premature deaths, and immunisation should set alarm bells ringing for policy makers about the effects of cuts to public health and early years services.”

The analysis looked at 16 child health measures in the UK and 14 other countries: …
Gut microbiota in toxicological risk assessment of drugs and chemicals: The need of hour
Authors: Ganesan Velmurugan
Journal: Gut Microbes (2018)

The advent of industrial revolution caused a large inflow of synthetic chemicals for medical, agricultural, industrial and other purposes in the world. In general, these chemicals were subjected to toxicological risk assessment for human health and ecology before release for public use. But today we are witnessing a negative impact of some of these chemicals on human health and environment indicating an underestimation of toxic effects by current risk assessment protocol. Recent studies established gut microbiota as one of the key player in intercession of toxicity of drugs and synthetic chemicals. Hence, the need of the hour is to include the assessment for microbiota specifically gut microbiota in human toxicological risk assessment protocol. Herewith we are proposing a framework for assessment of gut microbiota upon exposure to drugs or chemicals.
Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: prospective cohort study of half a million UK Biobank participants
Authors: Carlos A Celis-Morales, Paul Welsh, Donald M Lyall, Lewis Steell, Fanny Petermann, Jana Anderson, Stamatina Iliodromiti, Anne Sillars, Nicholas Graham, Daniel F Mackay, Jill P Pell, Jason M R Gill, Naveed Sattar, Stuart R Gray
Journal: BMJ (2018)

Abstract Objective To investigate the association of grip strength with disease specific incidence and mortality and whether grip strength enhances the prediction ability of an established office based risk score. Design Prospective population based study. Setting UK Biobank. Participants 502 293 participants (54% women) aged 40-69 years. Main outcome measures All cause mortality as well as incidence of and mortality from cardiovascular disease, respiratory disease, chronic obstructive pulmonary disease, and cancer (all cancer, colorectal, lung, breast, and prostate). Results Of the participants included in analyses, 13 322 (2.7%) died over a mean of 7.1 (range 5.3-9.9) years’ follow-up. In women and men, respectively, hazard ratios per 5 kg lower grip strength were higher (all at P&lt;0.05) for all cause mortality (1.20, 95% confidence interval 1.17 to 1.23, and 1.16, 1.15 to 1.17) and cause specific mortality from cardiovascular disease (1.19, 1.13 to 1.25, and 1.22, 1.18 to 1.26), all respiratory disease (1.31, 1.22 to 1.40, and 1.24, 1.20 to 1.28), chronic obstructive pulmonary disease (1.24, 1.05 to 1.47, and 1.19, 1.09 to 1.30), all cancer (1.17, 1.13 to 1.21, 1.10, 1.07 to 1.13), colorectal cancer (1.17, 1.04 to 1.32, and 1.18, 1.09 to 1.27), lung cancer (1.17, 1.07 to 1.27, and 1.08, 1.03 to 1.13), and breast cancer (1.24, 1.10 to 1.39) but not prostate cancer (1.05, 0.96 to 1.15). Several of these relations had higher hazard ratios in the younger age group. Muscle weakness (defined as grip strength &lt;26 kg for men and &lt;16 kg for women) was associated with a higher hazard for all health outcomes, except colon cancer in women and prostate cancer and lung cancer in both men and women. The addition of handgrip strength improved the prediction ability, based on C index change, of an office based risk score (age, sex, diabetes diagnosed, body mass index, systolic blood pressure, and smoking) for all cause (0.013) and cardiovascular mortality (0.012) and incidence of cardiovascular disease (0.009). Conclusion Higher grip strength was associated with a range of health outcomes and improved prediction of an office based risk score. Further work on the use of grip strength in risk scores or risk screening is needed to establish its potential clinical utility.
Development of gene expression signatures characterizing the tumor-immune interaction.
Authors: Patrick Danaher, Sarah Warren, Alessandra Cesano
Journal: Journal of Clinical Oncology (2018)

205 Background: The efficacy of anti-tumor immunity depends on diverse factors, including not just abundance of immune cell populations but also activities of those populations and of tumor cells. Many of these processes are onerous to assay, but all are reflected in a tumor’s gene expression profile. Using a novel method, we develop gene expression signatures measuring a variety of biological processes underlying the tumor-immune interaction. These signatures fall into categories including antigen availability, structural barriers to immune infiltration, inhibitory signaling by both immune and tumor cells, inhibitory metabolism, pro-immune signaling, killing of tumor cells, tumor receptiveness to immune signaling, and tumor proliferation and death. Methods: We develop a method to train signatures of biological processed by synthesizing biological knowledge and large gene expression datasets. For a given process, we use literature searches and expert knowledge to derive lists of candidate genes. We then evaluate the co-expression of these candidate genes in data from The Cancer Genome Atlas (TCGA), discarding genes whose co-expression patterns are incompatible with their measuring their putative biological process. This approach safeguards the interpretability of our signatures: we only report signatures whose genes show evidence for measuring the desired biology. Finally, we further exploit co-expression patterns to obtain optimal weights for each signature gene. Results: We attempted to train signatures of over 30 biological processes involved in immune oncology. Of these, 17 candidate gene sets displayed sufficient evidence for measuring their putative biology. We show these signatures provide granular but intelligible descriptions of both immunotherapy datasets and single samples. We find they improve power in differential expression analyses and in training of predictors of drug response. Conclusions: The signatures we derive convert gene expression data into measurements of biological processes central to immune oncology, and they improve statistical power and interpretation of results in immunotherapy studies. Our training procedure ensures these signatures measure their intended biology.
I am an Indian doctor who married a British doctor and came to the UK on a permanent settlement spouse visa. What are my career prospects in the UK with the new work permit rules?
Authors: Shaaz Mahboob
Journal: BMJ (2006)

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. <b>www.bmjcareers.com/advicezone</b>
Patient-reported anxiety with localized prostate cancer treated with stereotactic body radiation therapy (SBRT).
Authors: Nima Aghdam, Abigail Pepin, Colin Johnson, Malika Danner, Marilyn Ayoob, Thomas M. Yung, Siyuan Lei, Brian Timothy Collins, Anatoly Dritschilo, Simeng Suy, John Lynch, Sean P. Collins
Journal: Journal of Clinical Oncology (2018)

52 Background: Anxiety is a common aliment among elderly men. It may be negatively impacted by the diagnosis of cancer. Effective cancer treatment may alleviate anxiety. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire, which evaluates patient reported anxiety. Using the ELD14 questionnaire, this study assesses the trends in prostate cancer patient’s anxiety before and after treatment with SBRT. Methods: All patients with localized prostate cancer who received SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess quality of life before and following treatment. Initially, approximately 267 patients (median age of 70) responded to the ELD14 questionnaire. This study is focused on questions related to patient’s anxiety regarding their families, future, health and end of life. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Prior to treatment, 19% of patients felt quite a bit or very much worried about their families coping with their illness. This decreased to 9% at 24 months post-SBRT (p = 0.007). Initially, 27% of patients reported concerns for the future of their families, which subsequently decreased to 20% at 24 months (p = 0.15). At initial consult, 32% of patients reported being worried about their future health. This decreased to 13% at 24 months (p &lt; 0.001). Twenty percent of patient reported concern about their future at initial consult; this declined to 11% at 24 months (p = 0.03). And finally, self reported anxiety about end of life was 18% at the initial consult and 12% at 24 months (p = 0.16). Conclusions: Self-reported anxiety surrounding family, health and future is prevalent amongst prostate cancer patients at initial evaluation. Significant reduction in anxiety is observed in our cohort post-SBRT. Further investigations in the causes of pre and post-treatment anxiety may offer valuable insight into preventable root causes and improvement in patient’s quality of life.
CLOPIDOGREL RESISTANCE IN PATIENTS UNDERGOING LEFT ATRIAL APPENDAGE CLOSURE WITH THE WATCHMAN DEVICE
Authors: Carola Gianni, Rodney Horton, Carolyn O’ Grady, Sanghamitra Mohanty, Chintan Trivedi, Domenico Della Rocca, Amin Al-Ahmad, John Burkhardt, G. Gallinghouse, Patrick Hranitzky, Javier Sanchez, Luigi Di Biase, Andrea Natale
Journal: Journal of the American College of Cardiology (2018)
P062 Significant decrease of t-cells but not macrophages in the synovium of patients with active rheumatoid arthritis after treatment with tocilizumab
Authors: K Chatzidionysiou, M Engström, E af Klint, A Hensvold, AI Catrina
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Tocilizumab (TCZ) is an anti-IL6R monoclonal antibody approved for the treatment of Rheumatoid Arthritis (RA). There is limited data on synovial tissue histology changes. <h3>Objectives</h3> The aim of this study was to evaluate the effect of TCZ on synovial cell populations and on citrullination. <h3>Methods</h3> 15 patients with definite RA, according to ACR 1987 criteria, independent of disease duration, were included. Synovial biopsies were obtained before and after 8 weeks of treatment with TCZ from all patients. We evaluated by immunohistochemistry (IHC) expression of citrullinated proteins (CP) and protein arginine deiminase (PAD) enzymes in synovial tissue before and after treatment with TCZ (1325:C03, 1325:B09, PAD2, PAD4). Negative controls were used for each antibody. Expression of CD68, CD3, CD20 and CD55 was also evaluated. Evaluation of all IHC variables was performed by two blinded independent observers using a semiquantitative score on a 0–3 scale (0, no staining; 1, low amounts of staining; 2, moderate amounts of staining; 3, high amounts of staining). Paired-wised Wilcoxon Signed Ranks Test was used to compare the median value before and after treatment. <h3>Results</h3> The median (IQR) age, disease duration, N. prior biologic DMARDs and DAS28 at baseline was 66 (58–79), 4 (1–13), 1 (0–2), 6 (5–7), respectively. 93% were female, 53% were RF +and 60% ACPA+, 53% had concomitant glucocorticoids and only 27% had concomitant conventional synthetic DMARDs. Significant reductions in DAS28, swollen and tender joint count (SJC and TJC, respectively), and acute phase reactants (ESR and CRP) were observed between baseline and 8 weeks (table 1). By IHC, TCZ induced significant decrease in the number of CD3, C03 and CD55, but not in the number of the other CP, PAD2, PAD4 and CD68 (table 1). No significant correlations between reduction in disease activity (by ΔDAS28, ΔSJC, ΔTJC, ΔESR, ΔCRP) and reduction in CP, CD68 or CD3 were found. <h3>Conclusions</h3> Treatment with IL6R blockade reduced the number of synovial tissue T cells. This was observed in the responders but not in non-responders. Significant reduction in citrullination as assessed by expression of 1325:C03 but not 1325:B09. No significant reduction in macrophages was observed. <h3>Disclosure of interest</h3> None declared