tbuckley/cabot-search huggingface dataset:
Host genetic variation and its microbiome interactions within the Human Microbiome Project
Authors: Raivo Kolde, Eric A. Franzosa, Gholamali Rahnavard, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J. Daly, Ramnik J. Xavier, Curtis Huttenhower
Journal: Genome Medicine (2018)

Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome.
Complaints against doctors continue to rise
Authors: Caroline White
Journal: BMJ (2013)

The number of complaints made about doctors to the professional regulator have continued to increase, figures from the General Medical Council show.1

A summary of the trends in fitness to practise procedures in 2012 was laid before the GMC’s council last week ahead of full publication in the forthcoming State of Medical Education and Practice report. The summary shows that complaints about doctors referred to the GMC rose by 18% in 2012, to 10 347. This is double the number made in 2007 (5168).

Complaints made by members of the public still make up the bulk (59%) of complaints, though …
CHARACTERISTICS AND CARDIOVASCULAR DISEASE EVENT RATES AMONG AFRICAN AMERICANS WHO MEET THE FOURIER INCLUSION CRITERIA
Authors: Lisandro Colantonio, Keri Monda, Robert Rosenson, Todd Brown, Katherine Mues, George Howard, Monika Safford, Larisa Yedigarova, Michael E. Farkouh, Paul Muntner
Journal: Journal of the American College of Cardiology (2018)
Genotyping of circulating tumor DNA in biliary tract cancer to reveal diagnostic and prognostic information.
Authors: Andreas Wolfgang Berger, Thomas Jens Ettrich, Daniel Schwerdel, Anna Dolnik, Florian Beuter, Tamara J. Blätte, Stefan A. Schmidt, Nora Stanescu, Jochen Steinacker, Ralf Marienfeld, Lars Bullinger, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2018)

291 Background: Biliary tract cancer (BTC) shows increasing incidence and is associated with a high mortality. Diagnosis is difficult due to the frequently occurring inaccessibility of the tumor for biopsy. Noninvasive approaches for (i) assessing and (ii) monitoring the tumor-specific molecular setup are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: Blood and tumor tissue samples from patients with locally advanced or metastatic BTC prior to and during palliative treatment were collected. Tumor tissue and corresponding ctDNA samples underwent targeted genotyping of the 15 most frequently mutated genes in BTC. Findings were correlated with clinical and imaging data. Results: 24 therapy naive patients with histologically confirmed BTC were included for analyses. The overall mutational concordance (blood/tissue) was 74% and 92% for intrahepatic tumors. The mean variant allele frequency (VAF) in tumor tissue of therapy naïve patients was significantly higher compared to the respective ctDNA (p = 0.0291). In turn, the sequencing depth for ctDNA was significantly deeper (p = 0.0001), enabling us to detect also rare variants. Mean ctDNA VAF at baseline significantly correlated with tumor load (Spearman, r = 0.4073, p = 0.0433) and, exclusively for intrahepatic tumors, also with progression-free survival (Spearman, r = -0.5878, p = 0.0386). During 1 st line palliative treatment, we detected a change in the mutational landscape in 36% of cases, Moreover, we had access to ctDNA samples of 5 pretreated patients. While ctDNA samples of therapy naïve patients (n = 23) showed a mean of 0.78 mutations per patient, ctDNA samples of pretreated patients (n = 5) exhibited a mean of 0.4 mutations (p = 0.5519). Conclusions: The molecular landscape of BTC is depicted in ctDNA which may enable to adapt diagnostic and therapeutic strategies to the specific molecular setup present at a certain time. In contrast, the use of targeted resequencing is likely to be insufficient for a comprehensive assessment of treatment induced BTC evolution. For this purpose, we suggest a more extensive analysis of ctDNA by broader sequencing applications and the incorporation of epigenetics.
Female doctors may outnumber male doctors by 2017
Authors: Matthew Billingsley
Journal: BMJ (2012)

The number of female doctors registered with the General Medical Council has exceeded the 100 000 mark for the first time, rising by 4.7% to 104 534 in 2011.

Female doctors now account for 43% of the total, and the GMC estimates that they will overtake male doctors registered in the United Kingdom between 2017 and 2022.

In its annual report The State of Medical Education and Practice in the UK , the GMC claims that “the growing proportion of female doctors may accelerate demands for more flexible working patterns” and that training programmes and employers will need to accommodate shifting …
I am doing postgraduate studies in microbiology in India. What exams do I need to do to work in the United Kingdom? Also, please advise me on the prospects of specialising in immunology
Authors: Andrew Wilson
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>
CORONARY FLOW IMPAIRMENT IN DOMINANT CORONARY ATRIAL BRANCHES IN ST-ELEVATION MYOCARDIAL INFARCTION PATIENTS AND ATRIAL ARRHYTHMIAS AT ONE-YEAR FOLLOW-UP
Authors: Jose Manuel Montero, Rachid Abou, Laurien Goedemans, Martin Schalij, Jeroen J. Bax, Victoria Delgado
Journal: Journal of the American College of Cardiology (2018)
Three in a bed—man, wife, and MMC
Authors: Lynne M Beattie
Journal: BMJ (2007)

We welcome your rapid responses, whether in direct response to an article in Career Focus or as a way of sharing your own ideas. As long as it isn9t libellous or offensive, we9ll post it on our website. We print a selection of rapid reponses here and the writer of the best each month wins an <i>Oxford Handbook</i> of their choice. Letter of the month prize is donated by OUP.
End non-essential use of antimicrobials in livestock
Authors: Alison Holmes, Mark Holmes, Thomas Gottlieb, Lance B Price, Arnfinn Sundsfjord
Journal: BMJ (2018)

A rational response by WHO to the crisis in antimicrobial resistance Tackling antimicrobial resistance (AMR) is a priority of the World Health Organization’s public health agenda, and in November 2017 the organisation launched guidelines on the use of medically important antimicrobials in the food production industry. Their unambiguous recommendations were that their routine use for animal growth promotion and disease prevention in healthy animals should be discontinued (box 1).1 In line with the global action plan on AMR,2 the aim is to help preserve the effectiveness of antimicrobials critical for human medicine. As a supranational body, WHO has taken the opportunity to put independent pressure on healthcare policy makers to now respond to its challenge. Box 1 ### Recommendations from WHO1 1. An overall reduction in use of all classes of medically important antimicrobials in food producing animals 2. Complete restriction of use of all classes of medically important antimicrobials in food producing animals for growth promotion 3. 3 Complete restriction of use of all classes of medically important antimicrobials in food producing animals for prevention of infectious diseases that have not yet been clinically diagnosed 4. 4a Suggest that antimicrobials classified as critically important for human medicine should not be used for control of the dissemination of a clinically diagnosed infectious disease identified within a group of food producing animals 5. 4b Suggest that antimicrobials classified as highest priority (see below) critically important for human medicine should not be used for treatment of food producing animals with a clinically diagnosed … RETURN TO TEXT
Applying to specialty training: considering the competition
Authors: Alison Carr, Joanne Marvell, John Collins
Journal: BMJ (2013)

As applications open for specialty training in 2014, information on the competition that candidates are likely to face should help applicants make realistic career decisions. Writing on behalf of the UK Medical and Dental Recruitment and Selection Career Planning Group, <b>Alison Carr</b>, <b>Joanne Marvell</b>, and <b>John Collins</b> look at the competition data and explore the choices available to applicants
Impact of Open access CT (OACT) for headache suspected of brain cancer in Lothian
Authors: Karolis Zienius, Robin Grant, Paul Brennan
Journal: Neuro-Oncology (2018)

Guidance to General Practitioners on referral for direct-access brain imaging, based on levels of risks for CNS malignancy (red/orange/yellow) are proposed. However, the effect of such guidance upon referral behaviour is unknown. We reviewed all Open-Access-Computed- Tomography (OACT) referrals for possible CNS malignancy from Lothian-based GPs for 2010–2015. 3302 OACTs were performed. We report initial findings on a total of 54 scans positive for brain tumour (rate 1.63%). 57% were females, mean age 62 years. 57% patients had contrast-enhanced scan. There were 7 high-grade gliomas, 4 low-grade tumours, 16 metastases, 8 pituitary, 17 meningioma, 1 CNS lymphoma, and 1 skull metastasis. Six patients whose initial report queried a tumour had a normal follow-up imaging. All 6 patients had initial non-contrast scan only. Headache was the commonest complaint for patients whose scan identified a brain tumour: 16 referrals for headache-alone, 12 for headache-plus-neurological deficit, 4 for headache-plus-cognitive deficit and 22 for focal/cognitive symptoms but no headache. Time to scan from a referral, reported in median days, was: 19, 12.5, 18.5 and 17, respectively. It was shorter for patients with a known history of cancer (median, 9) than without (18) (MW u, p=0.06). Overall, pre-diagnostic symptomatic interval (median weeks) was longest for patients with non-focal symptoms: 14.4, 7.3, 14.8 and 9.6, respectively. Thirty-one (59.6%) referrals were for red-flag, 14 (26.9%) for orange-flag, and 7 (13.5%) for yellow-flag symptoms. We are now reviewing all OACTs and will report the frequencies of normal and significant abnormal other than brain tumour scans and will perform correlation whether these findings relate to a particular presenting symptom. We will report the frequency of symptom groups belonging to a suggested criteria of presumed risk of CNS malignancy (Kernick et al). We will also calculate measures of diagnostic performance for each symptom groups based on 3 levels of risk.
Phase I/II trial of pembrolizumab in combination with binimetinib in unresectable locally advanced or metastatic triple negative breast cancer.
Authors: Saranya Chumsri, Mei-Yin Polley, Sarah L. Anderson, Ciara Catherine Maria O'Sullivan, Gerardo Colon-Otero, Keith L Knutson, E Aubrey Thompson, Alvaro Moreno-Aspitia
Journal: Journal of Clinical Oncology (2018)

TPS17 Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.
Design of SERS nanoprobes for Raman imaging: materials, critical factors and architectures
Authors: Mingwang Li, Yuanyuan Qiu, Chenchen Fan, Kai Cui, Yongming Zhang, Zeyu Xiao
Journal: Acta Pharmaceutica Sinica B (2018)

Raman imaging yields high specificity and sensitivity when compared to other imaging modalities, mainly due to its fingerprint signature. However, intrinsic Raman signals are weak, thus limiting medical applications of Raman imaging. By adsorbing Raman molecules onto specific nanostructures such as noble metals, Raman signals can be significantly enhanced, termed surface-enhanced Raman scattering (SERS). Recent years have witnessed great interest in the development of SERS nanoprobes for Raman imaging. Rationally designed SERS nanoprobes have greatly enhanced Raman signals by several orders of magnitude, thus showing great potential for biomedical applications. In this review we elaborate on recent progress in design strategies with emphasis on material properties, modifying factors, and structural parameters.
Selective Inhibition of Nucleocytoplasmic Transport Overcomes Ruxolitinib Resistance in Myelofibrosis
Authors: Dongqing Yan, Srinivas K. Tantravahi, Anthony D. Pomicter, Clinton C. Mason, Anna Senina, Qiang Wang, Jamshid Sorouri Khorashad, Hein Than, Phillip M. Clair, William L. Heaton, Anna M. Eiring, Josef T. Prchal, Sabina I. Swierczek, Erkan Baloglu, Sharon Shacham, Thomas O'Hare, Michael W. Deininger
Journal: Blood (2017)
FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity
Authors: Xiao-Qing Xiong, Zhi Geng, Bing Zhou, Feng Zhang, Ying Han, Ye-Bo Zhou, Jue-Jin Wang, Xing-Ya Gao, Qi Chen, Yue-Hua Li, Yu-Ming Kang, Guo-Qing Zhu
Journal: Metabolism (2018)
Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation — Positive Advanced Non–Small Cell Lung Cancer (CheckMate 370)
Authors: David R. Spigel, Craig Reynolds, David Waterhouse, Edward B. Garon, Jason Chandler, Sunil Babu, Paul Thurmes, Alexander Spira, Robert Jotte, Jin Zhu, Wen Hong Lin, George Blumenschein
Journal: Journal of Thoracic Oncology (2018)
Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells
Authors: Ronald A. Li, Wendy Keung, Timothy J. Cashman, Peter C. Backeris, Bryce V. Johnson, Evan S. Bardot, Andy O.T. Wong, Patrick K.W. Chan, Camie W.Y. Chan, Kevin D. Costa
Journal: Biomaterials (2018)
Effect of Combined Oral Contraceptives on Glycosylated Haemoglobin
Authors: Nigel Oakley, Wendy Rostron
Journal: Journal of the Royal Society of Medicine (1982)

Glycosylated haemoglobin (HbA), was measured in 164 Caucasian women aged 20-40 years who were using: (1) barrier contraceptive methods; (2) contraceptive pills with 30 micrograms ethinyloestradiol and 150 micrograms laevo-norgestrel; (3) contraceptive pills with 30-35 micrograms ethinyloestradiol and 0.5-1 mg norethisterone. Mean +/- 1 s.d. values for the three groups were 7.64 +/- 0.69, 7.56 +/- 0.56 and 7.27 +/- 0.74 respectively. Groups (1) and (2) did not differ significantly from one another but the mean value for group (3) was significantly lower than for the other groups (P less than 0.01). Age, percentage ideal body weight and smoking did not influence HbA, but the value was higher for parous than for nulliparous women (P = 0.02). These findings can be explained in terms of the known effects of oestrogens and progestogens on fasting blood glucose.
Update: Dura Mater Graft–Associated Creutzfeldt-Jakob Disease — Japan, 1975–2017
Authors: Ryusuke Ae, Tsuyoshi Hamaguchi, Yosikazu Nakamura, Masahito Yamada, Tadashi Tsukamoto, Hidehiro Mizusawa, Ermias D. Belay, Lawrence B. Schonberger
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.
Macrophages come on tap for liver fibrosis therapy
Authors: Malcolm R. Alison, Wey‐Ran Lin
Journal: Hepatology (2018)

1Centre for Tumour Biology, Barts Cancer InstituteBarts and The London School of Medicine and DentistryLondonUnited Kingdom 2Department of Gastroenterology & Hepatology, Linkou Chang Gung Memorial HospitalChang Gung University College of MedicineTaoyuanTaiwan
Guideline Update on Evaluation and Selection of Prosthetic Valves
Authors: Rick A. Nishimura, Federico Gentile, Robert O. Bonow
Journal: JAMA Cardiology (2018)

This synopsis of the 2017 focused update of the 2014 American Heart Association and American College of Cardiology guidelines for patients with valvular heart disease discusses new recommendations regarding the selection of prosthetic valves in patients with valvular heart disease.
Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa
Authors: Síle F. Molloy, Cecilia Kanyama, Robert S. Heyderman, Angela Loyse, Charles Kouanfack, Duncan Chanda, Sayoki Mfinanga, Elvis Temfack, Shabir Lakhi, Sokoine Lesikari, Adrienne K. Chan, Neil Stone, Newton Kalata, Natasha Karunaharan, Kate Gaskell, Mary Peirse, Jayne Ellis, Chimwemwe Chawinga, Sandrine Lontsi, Jean-Gilbert Ndong, Philip Bright, Duncan Lupiya, Tao Chen, John Bradley, Jack Adams, Charles van der Horst, Joep J. van Oosterhout, Victor Sini, Yacouba N. Mapoure, Peter Mwaba, Tihana Bicanic, David G. Lalloo, Duolao Wang, Mina C. Hosseinipour, Olivier Lortholary, Shabbar Jaffar, Thomas S. Harrison
Journal: New England Journal of Medicine (2018)

Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy.We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks.A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).