tbuckley/cabot-search huggingface dataset:
Role for Wnt Signaling in Retinal Neuropil Development: Analysis via RNA-Seq and In Vivo Somatic CRISPR Mutagenesis
Authors: Sumeet Sarin, Elizabeth Zuniga-Sanchez, Yerbol Z. Kurmangaliyev, Henry Cousins, Mili Patel, Jeanette Hernandez, Kelvin X. Zhang, Melanie A. Samuel, Marta Morey, Joshua R. Sanes, S. Lawrence Zipursky
Journal: Neuron (2018)
Cardiac Kir2.1 and Na <sub>V</sub> 1.5 Channels Traffic Together to the Sarcolemma to Control Excitability
Authors: Daniela Ponce-Balbuena, Guadalupe Guerrero-Serna, Carmen R. Valdivia, Ricardo Caballero, F. Javier Diez-Guerra, Eric N. Jiménez-Vázquez, Rafael J. Ramírez, André Monteiro da Rocha, Todd J. Herron, Katherine F. Campbell, B. Cicero Willis, Francisco J. Alvarado, Manuel Zarzoso, Kuljeet Kaur, Marta Pérez-Hernández, Marcos Matamoros, Héctor H. Valdivia, Eva Delpón, José Jalife
Journal: Circulation Research (2018)

Rationale: In cardiomyocytes, Na V 1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. Objective: The objective of this study was to test whether Na V 1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. Methods and Results: In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1 Δ314-315 or Kir2.1 R44A/R46A with wild-type (WT) Na V 1.5 WT in heterologous cells reduced inward sodium current compared with Na V 1.5 WT alone or coexpressed with Kir2.1 WT . In cell surface biotinylation experiments, expression of Kir2.1 Δ314-315 reduced Na V 1.5 channel surface expression. Glycosylation analysis suggested that Na V 1.5 WT and Kir2.1 WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of Na V 1.5 WT , and vice versa, whereas coexpression with Kir2.1 Δ314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1 Δ314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell–derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with Na V 1.5 WT and Kir2.1 WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1 WT , Na V 1.5 WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that Na V 1.5 WT channels interact with AP1 through the Na V 1.5 Y1810 residue, suggesting that, like for Kir2.1 WT , AP1 can mark Na V 1.5 channels for incorporation into clathrin-coated vesicles at the trans -Golgi. Silencing the AP1 ϒ-adaptin subunit in human induced pluripotent stem cell–derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. Conclusions: The Na V 1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of Na V 1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.
Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution
Authors: Mark A Phuong, Gusti N Mahardika
Journal: Molecular Biology and Evolution (2018)

To expand our capacity to discover venom sequences from the genomes of venomous organisms, we applied targeted sequencing techniques to selectively recover venom gene superfamilies and nontoxin loci from the genomes of 32 cone snail species (family, Conidae), a diverse group of marine gastropods that capture their prey using a cocktail of neurotoxic peptides (conotoxins). We were able to successfully recover conotoxin gene superfamilies across all species with high confidence (> 100× coverage) and used these data to provide new insights into conotoxin evolution. First, we found that conotoxin gene superfamilies are composed of one to six exons and are typically short in length (mean = ∼85 bp). Second, we expanded our understanding of the following genetic features of conotoxin evolution: 1) positive selection, where exons coding the mature toxin region were often three times more divergent than their adjacent noncoding regions, 2) expression regulation, with comparisons to transcriptome data showing that cone snails only express a fraction of the genes available in their genome (24-63%), and 3) extensive gene turnover, where Conidae species varied from 120 to 859 conotoxin gene copies. Finally, using comparative phylogenetic methods, we found that while diet specificity did not predict patterns of conotoxin evolution, dietary breadth was positively correlated with total conotoxin gene diversity. Overall, the targeted sequencing technique demonstrated here has the potential to radically increase the pace at which venom gene families are sequenced and studied, reshaping our ability to understand the impact of genetic changes on ecologically relevant phenotypes and subsequent diversification.
Older GPs are more likely to do out of hours work, Scottish survey finds
Authors: Caroline White
Journal: BMJ (2013)

GPs over the age of 55 take on roughly twice as much out of hours care as GPs under the age of 35, indicates the latest primary care workforce survey for Scotland.1

The survey drew on the responses of 631 general practices in Scotland—almost two thirds (64%) of the total number—for in-hours care and all 14 NHS boards for out of hours care, covering the 12 months to …
Tuberculosis re-treatment after exclusion of rifampicin resistance
Authors: Chen-Yuan Chiang, Arnaud Trébucq
Journal: European Respiratory Journal (2018)

We agree with Falzon et al. [1] that treatment of isoniazid-resistant tuberculosis (TB) is an important issue. The first-line re-treatment regimen for previously treated TB patients, which was known as the category II regimen, comprised 8 months of isoniazid, rifampicin and ethambutol supplemented by streptomycin for the initial 2 months, and pyrazinamide for the initial 3 months (2SHRZE/HRZE/5HRE). It was introduced in the collaborative programme of the International Union Against Tuberculosis and Lung Disease in which the first-line initial regimen for new TB patients was an 8-month regimen comprising 2 months of isoniazid, rifampicin, pyrazinamide and streptomycin, followed by 6 months of isoniazid and thioacetazone (2HRZS/6HT) [2]. At that time, the prevalence of multidrug-resistant (MDR)-TB among previously treated TB cases was relatively low and the challenge was mainly isoniazid resistance [3]. The category II regimen was designed to overcome isoniazid resistance and to reduce the risk of acquired resistance to rifampicin. It performed fairly well in settings where resistance to isoniazid predominated among previously treated TB patients [4]. However, with the wide use of a 6-month regimen including rifampicin throughout the whole treatment course (2HRZE/4HR) for new TB patients (category I regimen), the prevalence of rifampicin resistance among previously treated TB patients increased substantially [5], rendering the category II regimen ineffective and problematic. Once rifampicin resistance is excluded, it might be wiser to use the category II regimen in TB retreatment <http://ow.ly/KLJE30hDX0I>
Intrasubject multimodal groupwise registration with the conditional template entropy
Authors: Mathias Polfliet, Stefan Klein, Wyke Huizinga, Margarethus M. Paulides, Wiro J. Niessen, Jef Vandemeulebroucke
Journal: Medical Image Analysis (2018)

Image registration is an important task in medical image analysis. Whereas most methods are designed for the registration of two images (pairwise registration), there is an increasing interest in simultaneously aligning more than two images using groupwise registration. Multimodal registration in a groupwise setting remains difficult, due to the lack of generally applicable similarity metrics. In this work, a novel similarity metric for such groupwise registration problems is proposed. The metric calculates the sum of the conditional entropy between each image in the group and a representative template image constructed iteratively using principal component analysis. The proposed metric is validated in extensive experiments on synthetic and intrasubject clinical image data. These experiments showed equivalent or improved registration accuracy compared to other state-of-the-art (dis)similarity metrics and improved transformation consistency compared to pairwise mutual information.
Medical defence costs prevent GPs from taking on out-of-hours work, BMA says
Authors: Abi Rimmer
Journal: BMJ (2015)

The high cost of medical defence cover is making it uneconomic for general practitioners to participate in out-of-hours work, GPs have warned.

Delegates at the BMA’s Local Medical Committees (LMCs) conference in London on 22 May voted unanimously in favour of a motion that invited the government “to acknowledge that the cost of medical defence cover is making it uneconomic for GPs to participate in OOH [out-of-hours] or other non-GMS [general medical services] work.” It called on the …
PREDICTORS OF RIGHT VENTRICULAR RECOVERY IN PATIENTS SUPPORTED WITH VA-ECMO FOR ACUTE MASSIVE PULMONARY EMBOLISM
Authors: Mehrdad Ghoreishi, Chetan Pasrija, Jean Jeudy, Frances Boulos, Kristopher Deatrick, Bartley Griffith, Zachary Kon
Journal: Journal of the American College of Cardiology (2018)
mRNA-nanoparticles to enhance and track dendritic cell migration.
Authors: Adam Grippin, Elias Sayour, Brandon Wummer, Adam Monsalve, Tyler Wildes, Kyle Dyson, Duane Anthony Mitchell
Journal: Journal of Clinical Oncology (2018)

72 Background: Despite aggressive clinical interventions, glioblastoma (GBM) remains almost universally fatal. In a pilot, randomized, and blinded clinical trial, we recently demonstrated that administration of RNA-loaded dendritic cell (DC) vaccines was associated with significantly improved progression-free and overall survival in patients with GBM (Mitchell et al, Nature 2015). Furthermore, clinical outcomes correlated with migration of Indium-111-labeled DCs to vaccine-site draining lymph nodes (LNs) measured by SPECT/CT imaging. While these studies demonstrated that DC migration may be an important clinical biomarker for response to DC vaccination, the complexity and regulatory requirements associated with nuclear labeling to track DC migration limits widespread application of this technique. We have therefore developed RNA-loaded magnetic nanoparticles (RNA-NPs) to enhance DC migration to LNs and track that migration with a widely available imaging modality (i.e. MRI). Methods: Cationic liposomes were loaded with iron oxide nanoparticles with or without cholesterol modification. The resulting nanoparticles were complexed with RNA and used to transfect DCs ex vivo. RNA-NP-loaded DsRed+ DCs were then injected intradermally into mice and tracked noninvasively with T 2 -weighted 11T MRI before excision and quantification with flow cytometry. Results: In vitro experiments demonstrate that iron oxide loading does not reduce RNA-NP-mediated transfection of DCs. Additionally, replacement of cationic lipids with cholesterol increased RNA-NP transfection of the DC2.4 cell line and enhanced the T cell stimulatory capacity of treated bone marrow-derived dendritic cells (BMDCs). Compared to electroporation, RNA-NPs enhanced DC migration to lymph nodes and reduced T 2 MRI intensity in DC-bearing lymph nodes. Conclusions: This data suggests that iron oxide-loaded RNA-NPs enable noninvasive cell tracking with MRI and enhance DC migration to lymph nodes. We have further shown that inclusion of cholesterol in RNA-NPs augments the stimulatory capacity of transfected DCs. Future work will consider effects of RNA-NPs on antitumor immune responses and the utility of MRI-detected DC migration as a biomarker of vaccine efficacy.
STENTYS SELF EXPANDABLE DRUG-ELUTING STENT IN THE TREATMENT OF LEFT MAIN CORONARY ARTERY STENOSIS IN PATIENTS WITH DIABETES: ONE-YEAR FOLLOW-UP OF MULTICENTRE POLISH LM STENTYS DES REGISTRY LM-STENTYS REGISTRY
Authors: Wojciech Wanha, Maksymilian Mielczarek, Grzegorz Smolka, Tomasz Roleder, Dariusz Ciecwierz, Milosz Jaguszewski, Brunon Tomasiewicz, Jaroslaw Gorol, Michał Chmielecki, Stanislaw Bartus, Tomasz Pawlowski, Michal Kasprzak, Adam Sukiennik, Jacek Kubica, Andrzej Lekston, Eliano Navarese, Michal Hawranek, Krzysztof Reczuch, Marcin Gruchala, Andrzej Ochala, Wojciech Wojakowski
Journal: Journal of the American College of Cardiology (2018)
ACUTE EFFECTS OF CARDIAC SURGERY ON 25 (OH) VITAMIN D (VITD) LEVELS AND RESPONSE TO VITD SUPPLEMENTATION: PRIMARY RESULTS OF THE ASSESS-D STUDY
Authors: J. Brent Muhlestein, John R. Doty, Donald Lappe, Kirk Knowlton, Heidi May, Tyler Barker, John Carlquist, Kristin Konery, Shannon Inglet, Ben Chisum, Viet T. Le, Oxana Galenko, Jeffrey Anderson
Journal: Journal of the American College of Cardiology (2018)
Incidence, patterns of treatment, and survival among men newly diagnosed with advanced prostate cancer: An analysis of SEER-Medicare data.
Authors: Jennifer Lynn Beebe-Dimmer, Julie J. Ruterbusch, Kathleen A. Cooney, Kendra L. Schwartz, Adam Bolton, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2018)

265 Background: About 5% of men are newly-diagnosed with advanced stage prostate cancer (PCa) and experience far poorer survival compared to men diagnosed with local or regionally-advanced disease. PCa mortality is higher in African Americans (AA) compared to non-Hispanic whites (NHW), with a marginally higher proportion of AA men first diagnosed with advanced disease. Thus, we sought to describe recent trends in incidence, survival and patterns of treatment among men diagnosed with de novo AJCC stage IV PCa. Methods: SEER*Stat software was used to calculate age-adjusted rates and annual percent changes for PCa stratified by AJCC stage and race/ethnicity for men age 66 or older diagnosed 2004-2014. We then used the Surveillance, Epidemiology and End Results database linked to Medicare Claims files to identify men diagnosed with advanced PCa during same time period. We examined patterns of treatment among all eligible patients and by race/ethnicity. Results: Rates for AJCC stage I-III PCa among elderly men have significantly declined in recent years for both NHW and AA men (-5.8% APC, p&lt;0.001 for both), while rates for AJCC stage IV increased for NHW men (+1.5% APC, p=0.011) and decreased for NHB men (-1.8% APC, p=0.008). Of the 8,828 eligible patients identified from the SEER-Medicare database, 13% were AA, with a median survival of 32 months among all patients and survival significantly poorer among AA (p &lt; 0.0001). AA patients were also more likely to go without treatment (p &lt; 0.0001) compared to NHW patients, even after accounting for early mortality and TNM stage. The frequency of nearly all forms of treatment was lower among AA patients with the exception of orchiectomy, which was significantly higher (10.1% vs. 6.1%), and among Medicare Part D enrollees, the progesterone Megace (24.6% vs. 15.0%). Conclusions: Results from this study of Medicare patients diagnosed with advanced stage PCa suggest less aggressive treatment may contribute to the poorer survival observed in AA men. Understanding drivers of treatment-related decisions are critical in reducing racial disparities in survival among men with advanced PCa.
Can I enter a palliative medicine specialist registrar training scheme with the MRCPsych qualification?
Authors: Idris Baker
Journal: BMJ (2004)

<i>Got 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.</i>
GPs’ job satisfaction dips in later life while surgeons’ rises, researchers find
Authors: Abi Rimmer
Journal: BMJ (2016)

GPs become less positive about their job prospects the further they progress in their careers, while surgeons become more positive, researchers from the University of Oxford have found.1

The researchers surveyed 37 332 doctors in nine cohorts of medical graduates from 1974, 1983, 1988, 1993, 1996, 1999, 2000, 2002, and 2008. Questionnaires were sent to the doctors at different …
A Role for Hydrocortisone Therapy in Septic Shock?
Authors: Anthony F. Suffredini
Journal: New England Journal of Medicine (2018)

One of the first double-blind, multicenter trials of hydrocortisone in the management of severe infections involved 194 patients and was reported in 1963.1 The authors noted that "the role of adrenocorticosteroids in the management of infectious diseases has been a subject of much controversy."1 Although "corticosteroids depress resistance to infection by reducing inflammation … corticosteroids have been shown … to be antiendotoxic and antipyretic, and to influence vascular reactivity in a manner that might conceivably be beneficial to the infected individual." Nevertheless, the authors found that low-dose hydrocortisone did not improve the 44% overall mortality among these patients. During the . . .
The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
Authors: Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P. Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E. Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W. Herzog, Brian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S. Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R. Balfour Sartor, Deepak Saxena, George Miller
Journal: Cancer Discovery (2018)

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4
What is the prevalence of imaging-defined intra-articular hip pathologies in people with and without pain? A systematic review and meta-analysis
Authors: Joshua J Heerey, Joanne L Kemp, Andrea B Mosler, Denise M Jones, Tania Pizzari, Richard B Souza, Kay M Crossley
Journal: British Journal of Sports Medicine (2018)

Background Intra-articular hip pathologies are thought to be associated with the development of hip and groin pain. A better understanding of the relationship between symptoms and imaging findings may improve the management of individuals with intra-articular hip pathologies. Objective To undertake a systematic review and meta-analysis to determine the prevalence of intra-articular hip pathologies in individuals with and without pain. Methods Seven electronic databases were searched in February 2017 for studies investigating the prevalence of intra-articular hip pathologies using MRI, MRA or CT. Two independent reviewers conducted the search, study selection, quality appraisal and data extraction. Meta-analysis was performed when studies were deemed homogenous, with a strength of evidence assigned to pooled results. Results In general, studies were moderate to high risk of bias, with only five studies adjudged to be low risk of bias. The 29 studies reporting on the prevalence of intra-articular hip pathologies identified limited evidence of a labral tear prevalence of 62% (95% CI 47% to 75%) in symptomatic individuals, with moderate evidence identifying a labral tear prevalence of 54% (95% CI 41% to 66%) in asymptomatic individuals. Limited evidence demonstrated a cartilage defect prevalence of 64% (95% CI 25% to 91%) in symptomatic individuals, compared with moderate evidence of a cartilage defect prevalence of 12% (95% CI 7% to 21%) in asymptomatic individuals. Conclusion The prevalence of intra-articular hip pathologies is highly variable in both symptomatic and asymptomatic populations. The prevalence of intra-articular hip pathologies appears to be higher in symptomatic individuals. However, imaging-defined intra-articular hip pathologies are also frequently seen in asymptomatic individuals, highlighting a potential discordant relationship between imaging pathology and pain. PROSPERO registration number CRD42016035444 .
General practice is facing its biggest ever workforce crisis, BMA warns
Authors: Abi Rimmer
Journal: BMJ (2015)

General practice is experiencing the biggest workforce crisis “since its inception,” the BMA has warned.

Delegates at the BMA’s conference of local medical committees (LMCs) in London voted in favour of a motion calling on the government to ensure that GP funding, recruitment, and retention were tackled as its first priority for the NHS.

The motion also called on the government to ensure that “GPs who are leaving the profession early are supported to stay in practice” and that “all those wishing to …
VISCERAL ADIPOSITY IS A SIGNIFICANTLY STRONGER PREDICTOR OF DIABETES INCIDENCE IN MEN THAN IN WOMEN
Authors: Alexander Vonbank, Christoph Saely, Christina Lins, Daniela Zanolin, Andreas Leiherer, Philipp Rein, Axel Muendlein, Heinz Drexel
Journal: Journal of the American College of Cardiology (2018)
ELECTROCARDIOGRAPHIC SELVESTER SCORE IS ASSOCIATED WITH SUDDEN AND NON-SUDDEN CARDIAC DEATH: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY AND CARDIOVASCULAR HEALTH STUDY
Authors: David M. German, Erick A. Perez-Alday, Aron Bender, Jason Thomas, Christopher Hamilton, Srini Mukundan, Wendy Post, Scott Solomon, Elsayed Soliman, Nona Sotoodehnia, David Siscovick, Larisa Tereshchenko
Journal: Journal of the American College of Cardiology (2018)
Annexin V conjugated nanobubbles: A novel ultrasound contrast agent for in vivo assessment of the apoptotic response in cancer therapy
Authors: Tian Zhou, Wenbin Cai, Hengli Yang, Huizhong Zhang, Minghua Hao, Lijun Yuan, Jie Liu, Li Zhang, Yilin Yang, Xi Liu, Jianling Deng, Ping Zhao, Guodong Yang, Yunyou Duan
Journal: Journal of Controlled Release (2018)
BLEEDING EVENTS AND THEIR CONSEQUENCES ON CARDIOVASCULAR EVENTS, READMISSION AND NET CLINICAL BENEFIT
Authors: Philippe Steg, Deepak Bhatt, Stephen Ellis, Stefan Hohnloser, Eva Kleine, Matias Nordaby, Monika Simetzberger, Takeshi Kimura, Gregory Lip, Jonas Oldgren, Jurrien Ten Berg, Christopher Cannon, Hôpital Bichat
Journal: Journal of the American College of Cardiology (2018)