tbuckley/cabot-search huggingface dataset:
Time for high-burden countries to lead the tuberculosis research agenda
Authors: Madhukar Pai
Journal: PLoS Medicine (2018)

At long last, tuberculosis (TB) is getting the political attention that it deserves, being the leading infectious killer of humans today.In 2016, there were 10.4 million estimated new TB cases, with over 1.7 million deaths [1].The G20 declaration of July 2017 included TB in the context of the need to respond to the antimicrobial resistance threat, following the group's meeting in Hamburg, Germany [2].In November 2017, for the first time, a WHO Global Ministerial Conference on TB was held in Moscow, Russia, culminating in the Moscow Declaration to End TB [3].This year, in September, the United Nations General Assembly (UNGA) will hold the first-ever high-level meeting on the fight against TB [4].While the political attention brings much needed hope, other developments provide cause for worry.The United States government, the largest funder of TB control and research, is rapidly scaling back on overseas aid, slashing billions from global health and humanitarian assistance [5].Canada, despite its progressive policies, is spending substantially less on international aid than comparable G7 countries [6].And while there are considerable uncertainties, Brexit could have a major impact on European Union international development and humanitarian policies and is expected to challenge the EU's role as the world's leading donor [7].The case for funding global health in general, and TB in particular, in this political climate will lack for attention as long as wealthy donor countries focus their priorities on populist and nationalist demands or short-term outcomes of a transactional nature.It is therefore critical for countries most affected by TB to step up, show leadership, and invest in TB control as well as research.Take the case of Brazil, Russia, India, China, and South Africa (BRICS), which together account for 46% of all incident cases of TB and 40% of all TB-related mortality [1].With strong, if uneven, economic growth in BRICS, and their growing stature and leadership in the political arena, these countries are well placed to lead the charge against a disease that is a leading killer of their citizens and a huge drain on their economies [8].In fact, investments in TB control can lead to a huge return on investments for these countries [9].Commendably, there are signs of the BRICS stepping up to deal with TB, commensurate with their disease burden and economic and scientific prowess [8].The BRICS Leaders Xiamen Declaration (2017) specifically mentioned the need to improve surveillance of TB and also agreed to set up a TB research network [10].In fact, the BRICS are now major producers of TB research [11].While the US remains the top producer of TB research in the past 2 decades, India and China have emerged as the second and third leading producers of TB research in recent years [11].Further, bibliometric analyses show that the average year-on-year increase in TB publications from the BRICS countries was, in the past decade, nearly double the overall year-on-year increase across all countries [11].
Identifying tumour associated macrophages and microglia in an experimental glioblastoma model
Authors: Amir Saam Youshani, Kenny Yu, Fiona Wilkinson, Claire O’leary, Peter Cook, Aiyin Liao, Omar Pathmanaban, Chris Waugh, Hannah Shorrock, Andrew Macdonald, Federico Roncaroli, Ian Kamaly-asl, Brian Bigger
Journal: Neuro-Oncology (2018)

Glioblastoma is the most aggressive primary brain cancer, with 14.6 months median survival. Tumour associated macrophages and microglia (TAMM) populate upto 40% of the tumour bulk and represent potential immunotherapy targets. Characterising functional roles of TAMM subpopulations remains elusive due to limitations of existing mouse models and cross-reactive cell-surface markers. We identify a new marker-set using flow cytometry that distinguishes between peripheral macrophages and brain microglia in glioblastoma. Using non-myeloablative busulfan conditioning, we transplant mice expressing the pan leukocyte epitope CD45.1 with haematopoietic donor cells expressing congenic CD45.2, without damaging the recipient blood-brain barrier. Once 90% bone marrow chimerism is achieved at 12 weeks with no brain macrophage repopulation, we stereotactically implant GL261 murine glioblastoma cells into brain of chimeric mice, recapitulating normal tumour development. Brain flow cytometry using a 15-marker panel was then used to identify different immune cell populations and characterise TAMM subpopulations. We identify multiple immune populations migrating to tumours, and demonstrate that marker sets such as CD11b/CD45 and Siglec-H/CX3CR1, used to distinguish between microglia and macrophages, have significant co-staining from other leukocyte populations (both donor and recipient). Importantly we identify a novel 4-marker set that separates TAMM into four subpopulations with ≥ 90% donor/recipient purity, including monocytes, undifferentiated and differentiated macrophages, and microglia. In conclusion, we have developed a novel chimeric mouse model that achieves superior levels of peripheral chimeras, yet retains a homeostatic brain. Our results also highlighted a new 4-marker approach to subcategorising TAMM. RNA sequencing of TAMM subpopulations and downstream transcriptional analysis will provide the first insight into the functional role of TAMM. Further work will necessitate applying this marker set to human glioblastoma specimens, and validate our findings from an experimental glioblastoma model.
Incidence, severity and factors associated with diarrhoea in phase I oncology studies: experience of 1002 consecutive cases.
Authors: Nikolaos Diamantis, Samuel John Harris, Anastasia Constantinidou, Vasiliki Michalarea, Mariane Sousa Fontes, Maria Jose de Miguel Luken, Tejaskumar Laxmanbhai Avaiya, Ann Petruckevitch, Donald Flohr, Janet Hanwell, Dionysios Papadatos-Pastos, Juanita Lopez, Timothy Anthony Yap, Johann S. De Bono, Udai Banerji
Journal: Journal of Clinical Oncology (2016)

2568 Background: Diarrhea is a common toxicity related to cancer treatment. Diarrhea occurs at different degrees of severity both within and outside the dose limiting toxicity window, influencing the dose and schedule of novel anticancer drugs. We aimed to assess the incidence, severity and factors predisposing to diarrhea in patients (pts) enrolled in phase I studies. Methods: This is a retrospective study of 1002 separate phase I trial pt-cases treated at the Royal Marsden Hospital Drug Development Unit between January 2010 and December 2014. Data were collected from our electronic records for consecutive pts participating in 80 different phase I trials. Results: The incidence of diarrhea was 32.1%. Grade 1-5 diarrhea was reported in 21.9%, 6.3%, 3.1%, 0.1% and 0.1% pt-cases respectively. 69.5% episodes of diarrhea were reported as drug related. 5.6% of pts had a specific trial intervention due to diarrhea such as dose interruption or withdrawal from study. Time on study was not significantly different in pts who developed diarrhea (2.06 vs 1.9 months p = 0.14). The incidence of diarrhea was influenced by the primary site of the tumor (abdominal vs non abdominal, 35.3% vs 27.1%, p = 0.01) and the primary organ site specifically, p < 0.001. Pts who had previous abdominal surgery (n = 472) or colostomies (n = 71) had significantly higher incidence of diarrhea compared to those who did not, 38.4% vs 27.3% p = 0.0002 and 49% vs 31.3% p = 0.003 respectively. The administration route, (po vs iv, 38.4% vs 27.3% p = 0.008), trial design, (single agent vs combination, 29.2% vs 48%, p < 0.0001) and study drug mechanism of action (PI3K inh. vs other, 36.6% vs 28.2%, p = 0.002) also had a significant effect. Previous pelvic radiotherapy did not significantly influence the incidence of diarrhea. Conclusions: Diarrhea is a significant toxicity reported in approximately one third of pts enrolled in phase I clinical trials. Factors predisposing to diarrhea included colostomies, abdominal surgery, administration route and trial design. These data from across a wide variety of phase I studies should be used as benchmark of the incidence of diarrhea to inform trial design, inclusion and exclusion criteria of future early phase studies.
Dermatopathic Lymphadenitis
Authors: William Makis, Marc Hickeson, Miriam Blumenkrantz
Journal: Clinical Nuclear Medicine (2010)

Dermatopathic lymphadenitis (also known as lipomelanotic reticulosis, or Pautrier–Woringer disease) is a rare type of benign lymphatic hyperplasia associated with a variety of exfoliative or eczematoid type inflammatory erythrodermas. The axillary and inguinal regions are most commonly affected, although occasionally it can present in the head and neck as well. On histologic examination, the affected lymph nodes contain melanin and fat-laden reticular cells. This is a case of a 10-year-old boy with a history of severe eczema, who presented with enlarged lymph nodes. F-18 FDG PET/CT imaging showed intensely FDG-avid lymph nodes in the cervical, axillary, and inguinal regions and a diagnosis of lymphoma was suggested; however, histopathology revealed dermatopathic lymphadenitis. This entity is a potential pitfall in the F-18 FDG PET/CT evaluation of lymphoma and should be considered in the differential diagnosis, especially in individuals with a history of inflammatory erythrodermas. To our knowledge, this is the first report of F-18 FDG PET/CT imaging of dermatopathic lymphadenitis mimicking lymphoma.
What are the criteria for shortlisting someone for a senior house officer post in medicine?
Authors: Alan Watson
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.
In vitro cytocompatibility evaluation of poly(octamethylene citrate) monomers toward their use in orthopedic regenerative engineering
Authors: Chuying Ma, Ethan Gerhard, Qiaoling Lin, Silun Xia, April Dawn Armstrong, Jian Yang
Journal: Bioactive Materials (2018)

Citrate based polymer poly(octamethylene citrate) (POC) has shown promise when formulated into composite material containing up to 65 wt% hydroxylapatite (HA) for orthopedic applications. Despite significant research into POC, insufficient information about the biocompatibility of the monomers 1,8-Octanediol and Citrate used in its synthesis is available. Herein, we investigated the acute cytotoxicity, immune response, and long-term functionality of both monomers. Our results showed a cell-type dependent cytotoxicity of the two monomers: 1,8-Octanediol induced less acute toxicity to 3T3 fibroblasts than Citrate while presenting comparable cytotoxicity to MG63 osteoblast-like cells; however, Citrate demonstrated enhanced compatibility with hMSCs compared to 1,8-Octanediol. The critical cytotoxic concentration values EC30 and EC50, standard for comparing cytotoxicity of chemicals, were also provided. Additionally, Citrate showed slower and less inhibitory effects on long-term hMSC cell proliferation compared with 1,8-Octanediol. Furthermore, osteogenic differentiation of hMSCs exposure to Citrate resulted in less inhibitory effect on alkaline phosphatase (ALP) production. Neither monomer triggered undesired pro-inflammatory responses. In combination with diffusion model analysis of monomer release from cylindrical implants, based on which the maximum concentration of monomers in contact with bone tissue was estimated to be 2.2 × 10-4 mmol/L, far lower than the critical cytotoxic concentrations as well as the 1,8-Octanediol concentration (0.4 mg/mL or 2.7 mmol/L) affecting hMSCs differentiation, we provide strong evidence for the cytocompatibility of the two monomers degraded from citrate-based composites in the orthopedic setting.
Put out to pasture: what is our duty of care to the retiring professional footballer? Promoting the concept of the ‘exit health examination’ (EHE)
Authors: Sean Carmody, Christopher Jones, Aneil Malhotra, Vincent Gouttebarge, Imtiaz Ahmad
Journal: British Journal of Sports Medicine (2018)

Retired professional footballers are at a significantly increased risk of several health problems including osteoarthritis,1 mental health conditions2 and difficulties pertaining to suboptimal lifestyle choices.3 The aim of this editorial is to highlight the health issues faced by players in retirement, to advance the concept of the ‘exit health examination’ (EHE) and to promote the duty of care that clinicians, clubs and governing bodies have to ensure that the risk of poor long-term health outcomes is minimised.

Professional footballers are prone to recurrent and severe musculoskeletal injuries, which can occasionally be career-ending.4 Although these can in themselves increase the likelihood of developing osteoarthritis, they may also require surgical intervention, which heightens the risk.

Several studies have highlighted the increased prevalence of hip, knee and ankle osteoarthritis among ex-footballers compared with the general population, with much earlier onset of disease and increased likelihood of joint replacement reported.1 The presence of osteoarthritis in ex-footballers is associated with a poorer health-related quality of life and an increased risk of mental health …
Slit–Robo signalling in heart development
Authors: Juanjuan Zhao, Mathilda T M Mommersteeg
Journal: Cardiovascular Research (2018)

The Slit ligands and their Robo receptors are well-known for their roles during axon guidance in the central nervous system but are still relatively unknown in the cardiac field. However, data from different animal models suggest a broad involvement of the pathway in many aspects of heart development, from cardiac cell migration and alignment, lumen formation, chamber formation, to the formation of the ventricular septum, semilunar and atrioventricular valves, caval veins, and pericardium. Absence of one or more of the genes in the pathway results in defects ranging from bicuspid aortic valves to ventricular septal defects and abnormal venous connections to the heart. Congenital heart defects are the most common congenital malformations found in life new-born babies and progress in methods for large scale human genetic testing has significantly enhanced the identification of new causative genes involved in human congenital heart disease. Recently, loss of function variants in ROBO1 have also been linked to ventricular septal defects and tetralogy of Fallot in patients. Here, we will give an overview of the role of the Slit-Robo signalling pathway in Drosophila, zebrafish, and mouse heart development. The extent of these data warrant further attention on the SLIT-ROBO signalling pathway as a candidate for an array of human congenital heart defects.
QUANTITATIVE ANALYSIS OF PAPILLARY MUSCLES AND TRABECULAE IN ELITE, YOUNG AND MASTERS ATHLETES WITH CARDIAC MAGNETIC RESONANCE IMAGING
Authors: Ibolya Csecs, Csilla Czimbalmos, Nora Sydo, Orsolya Kiss, Petra Merkely, Vencel Juhasz, Ferenc Suhai, Attila Toth, Bela Merkely, Hajnalka Vágó
Journal: Journal of the American College of Cardiology (2018)
OCCUPATIONAL ENVIRONMENTAL EXPOSURES AND CARDIAC STRUCTURE AND FUNCTION: THE ECHOCARDIOGRAPHIC STUDY OF LATINOS (ECHO-SOL)
Authors: Melissa Burroughs Pena, Catherine M. Bulka, Katrina Swett, Krista Perreira, Mayank Kansal, Matthew Loop, Martha Daviglus, Carlos Rodriguez
Journal: Journal of the American College of Cardiology (2018)
Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent
Authors: Joseph Lachance, Ali J. Berens, Matthew E.B. Hansen, Andrew K. Teng, Sarah A. Tishkoff, Timothy R. Rebbeck
Journal: Cancer Research (2018)

Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer-associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.
Predictors of pathologic response after radical cystectomy for muscle invasive bladder cancer: A population-based analysis.
Authors: Shane M. Pearce, Akbar Ashrafi, Matthew Winter, Saum Ghodoussipour, Daniel Zainfeld, Inderbir Gill, Mihir Desai, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2018)

503 Background: Neoadjuvant chemotherapy (NAC) improves overall survival (OS) for patients with muscle invasive bladder cancer (MIBC) undergoing radical cystectomy (RC), possibly through an increase in pathologic complete response (CR), defined as a pathologic stage T0 (pT0). We sought to identify predictors of CR for MIBC. Methods: The National Cancer Database from 2004 to 2013 was used to identify patients with cT2-4cN0cM0 urothelial cell carcinoma treated with RC. Patients were grouped based on pathology as CR (pT0), partial response (PR – pTa/Tis/T1) or no response (NR - pT2 or higher). Predictors of NAC and CR were identified with multivariable logistic regression. Cox proportional hazards model was used to compare OS based on cT stage, receipt of NAC and pathologic response. Results: The study population included 10,820 patients and NAC was administered in 16.4%. Use of NAC was associated with higher cT stage (p &lt; 0.01) and increased over time (10% from 2003-2007 vs. 24% from 2011-2013, p &lt; 0.01). Predictors of NAC use on multivariable analysis include younger age, lower comorbidity score, treatment at an academic center, and diagnosis from 2011-2013 (p &lt; 0.01). Overall, CR was achieved in 3.3% without NAC and 16.3% with NAC (p &lt; 0.01). NAC improved 5-year OS for all cT stages, however the survival benefit was only observed among those achieving CR (p &lt; 0.01). Multivariable Cox regression demonstrates that both PR (HR 0. 58, p &lt; 0.01) and CR (OR 0.26, p &lt; 0.01) were independently associated with improved OS among those treated with NAC. Multivariable analysis identified age (OR 0.98, p &lt; 0.01) and increased clinical stage (cT3: OR 0.47, p &lt; 0.01; cT4 OR 0.54, p &lt; 0.01) as negative predictors of CR. Utilization of NAC (OR 4.82 p &lt; 0.01), academic institution, and diagnosis 2011-2013 (OR 1.92, p &lt; 0.01) increased the odds of CR. Conclusions: Use of NAC increased over time and CR occurred in 16% of patients who received NAC. Treatment at an academic center, diagnosis from 2011-2013 and use of NAC were independently associated with CR, while increased age and clinical stage were negative predictors of CR. PR and CR are independently associated with improved OS relative to non-responders.
Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3
Authors: K.A. Papp, K.B. Gordon, R.G. Langley, M.G. Lebwohl, A.B. Gottlieb, S. Rastogi, R. Pillai, R.J. Israel
Journal: British Journal of Dermatology (2018)

Biologics are being used increasingly to treat moderate‐to‐severe psoriasis. Efficacy may differ in patients with previous exposure to biologics. To investigate the impact of previous biologic exposure on the efficacy and safety of brodalumab and ustekinumab in patients with moderate‐to‐severe plaque psoriasis. Two placebo‐ and ustekinumab‐controlled phase III clinical trials. There was an initial 12‐week induction phase where patients were treated with brodalumab [210 mg or 140 mg every 2 weeks (Q2W)], ustekinumab or placebo. Efficacy end points included ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout. In total, 493 patients [334 (27%) brodalumab 210 mg Q2W and 159 (26%) ustekinumab] had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40·9% and 39·5% of biologic‐naive and ‐experienced patients achieved PASI 100 at week 12, compared with 21·1% and 17·0% with ustekinumab (both P <0·001). In patients where prior biologics had been successful or failed, 41·7% and 32·0% achieved PASI 100, compared with 21·1% and 11·3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous treatment with biologics. The efficacy of brodalumab 210 mg Q2W was similar regardless of prior biological therapy (P =0·31, 0·32 and 0·64 for PASI 75, 90 and 100, respectively). Almost twice as many patients achieved PASI 100 or complete clearance with brodalumab at week 12 compared with ustekinumab; the differences were most noticeable where previous biologics had failed. Both treatments were well tolerated.
“No weekend working” is used to encourage UK consultants to move down under
Authors: Abi Rimmer
Journal: BMJ (2015)

The BMA has described an email from a medical recruitment company offering consultant radiologists a 40 hour, Monday to Friday, working week in Australia as a “spectacular own goal by Jeremy Hunt.”

Head Medical, which is based in Edinburgh, emailed 280 consultant radiologists who had registered with its service, offering them a better work-life balance in Australia. The email was sent after the health secretary warned that a new contract could remove consultants’ ability to opt out of non-emergency work at weekends.1

Consultant clinical radiologists …