tbuckley/cabot-search huggingface dataset:
CRISPRO: identification of functional protein coding sequences based on genome editing dense mutagenesis
Authors: Vivien A. C. Schoonenberg, Mitchel A. Cole, Qiuming Yao, Claudio Macias-Treviño, Falak Sher, Patrick G. Schupp, Matthew C. Canver, Takahiro Maeda, Luca Pinello, Daniel E. Bauer
Journal: Genome biology (2018)

CRISPR/Cas9 pooled screening permits parallel evaluation of comprehensive guide RNA libraries to systematically perturb protein coding sequences in situ and correlate with functional readouts. For the analysis and visualization of the resulting datasets, we develop CRISPRO, a computational pipeline that maps functional scores associated with guide RNAs to genomes, transcripts, and protein coordinates and structures. No currently available tool has similar functionality. The ensuing genotype-phenotype linear and three-dimensional maps raise hypotheses about structure-function relationships at discrete protein regions. Machine learning based on CRISPRO features improves prediction of guide RNA efficacy. The CRISPRO tool is freely available at gitlab.com/bauerlab/crispro .
Abstract 15349: Circulating Glycosphingolipids Primarily Correlate With LDL-C but Not HDL-C or TG and Are Associated With Disease Severity in Acute Myocardial Infarction
Authors: Sock Hwee Tan, Ghim Siong Ow, Leonardo P de Carvalho, Jianhong Ching, Sock Cheng Poh, Chee Tang Chin, A. Mark Richards, Richard Troughton, Alan Y Fong, Bryan P Yan, Aruni Seneviratna, XiaoXun Yang, Vladimir A Kuznetsov, Jean-Paul Kovalik, Scott A Summers, Mark Y Chan
Journal: Circulation (2016)

Introduction: Circulating cholesterol remains a principal target of therapies aimed at reducing ischemic events after acute myocardial infarction (AMI). Studies have shown that sphingolipids, a cla...
Begoña Anne Bovill
Authors: Simon Rose
Journal: BMJ (2018)

An article about leprosy in the World of Wonder children’s magazine triggered Begona Anne Bovill’s early interest in medicine and infectious disease. She went to the Royal Free Hospital School of Medicine, where she revelled in student life, designing the logo for Rag Week, performing in shows, and partying as well as studying. Inexplicably she fell for a fellow student of different disposition, with whom she published a few eclectic papers, including an excellent suggestion to treat iron overload in haemochromatosis with hookworms—passed over by The BMJ for its Christmas edition. After an elective in Peru, she cut her teeth on busy house jobs and, as senior house officer at Whipps Cross Hospital, was inspired by great general hospital physicians, such as Drs Partridge and Glick, whose teaching and the huge exposure to general medicine made passing the membership examination for the Royal College of Physicians a formality.

Half Spanish and bilingual, Begona married me in a hilltop chapel in Andalucia, with a full flamenco …
Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss
Authors: Kimito Hirai, Hisako Furusho, Kiichi Hirota, Hajime Sasaki
Journal: International Journal of Oral Science (2018)

Hypoxia (low oxygen level) is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1 (HIF-1). Hypoxia interferes degradation of HIF-1 alpha subunit (HIF-1α), leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit (HIF-1β) and subsequent activation of HIF-1 pathway. Apical periodontitis (periapical lesion) is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a well-characterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine (DMOG) and adenovirus-induced constitutively active HIF-1α (CA-HIF1A). Both DMOG and CA-HIF1A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B (NF-κB) and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.
Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data
Authors: Carolyn Taylor, Paul McGale, Dorthe Brønnum, Candace Correa, David Cutter, Frances K. Duane, Bruna Gigante, Maj-Britt Jensen, Ebbe Lorenzen, Kazem Rahimi, Zhe Wang, Sarah C. Darby, Per Hall, Marianne Ewertz
Journal: Journal of Clinical Oncology (2018)

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( P trend &lt; .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were −5.0, −2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( P trend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.
Michael Asher Weingarten
Authors: Susan Weingarten
Journal: BMJ (2018)

Michael Asher (“Micky”) Weingarten was professor of family medicine at Tel Aviv University and a key founder of the new Bar-Ilan Faculty of Medicine in Safed in Galilee.

Micky was born in 1947 in Golders Green, London to a family of Jewish refugees from Nazi Germany. He was educated at the City of London School; Jews’ College, London; Merton College, Oxford; and University College Hospital, London. 

He emigrated to Israel and began his training as a family doctor in 1973. A few weeks later, the Yom Kippur war broke out, and he found himself, a very junior hospital doctor, as the “consultant” in internal medicine to the burns unit, for the wounded soldiers brought in from the Suez Canal. After this war, he continued his GP training in the deprived development town of Bet Shean, living on a local kibbutz. When called up to the army, he served as a doctor on the helicopter rescue unit, where he did reserve duty for 20 years. During the Lebanon war, he was once in command of a helicopter …
Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis
Authors: C. E. Rosenberg, M. K. Mingler, J. M. Caldwell, M. H. Collins, P. C. Fulkerson, D. W. Morris, V. A. Mukkada, P. E. Putnam, T. Shoda, T. Wen, M. E. Rothenberg
Journal: Allergy (2018)

Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses.This case-control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non-EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1-IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts.Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0-13.1 mg/g protein] vs 0.2 mg/g protein [0.1-0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression.These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally.
Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort
Authors: Stephanie M. Engel, Gro D. Villanger, Rachel C. Nethery, Cathrine Thomsen, Amrit K. Sakhi, Samantha S.M. Drover, Jane A. Hoppin, Pal Zeiner, Gun Peggy Knudsen, Ted Reichborn-Kjennerud, Amy H. Herring, Heidi Aase
Journal: Environmental Health Perspectives (2018)

There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype.We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (n=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n=553) from the MoBa population was obtained.In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.In this population-based case-control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358.
Cognition as a Window into Neuronal Population Space
Authors: Douglas A. Ruff, Amy M. Ni, Marlene R. Cohen
Journal: Annual Review of Neuroscience (2018)

Understanding how cognitive processes affect the responses of sensory neurons may clarify the relationship between neuronal population activity and behavior. However, tools for analyzing neuronal activity have not kept up with technological advances in recording from large neuronal populations. Here, we describe prevalent hypotheses of how cognitive processes affect sensory neurons, driven largely by a model based on the activity of single neurons or pools of neurons as the units of computation. We then use simple simulations to expand this model to a new conceptual framework that focuses on subspaces of population activity as the relevant units of computation, uses comparisons between brain areas or to behavior to guide analyses of these subspaces, and suggests that population activity is optimized to decode the large variety of stimuli and tasks that animals encounter in natural behavior. This framework provides new ways of understanding the ever-growing quantity of recorded population activity data.
Surgical Procedures for Patients With Severe Obesity
Authors: Tyler Cohn, Aurora Pryor, Konstantinos Spaniolas
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Long‐term survival and loss in expectancy of life in a population‐based cohort of 7114 patients with diffuse large B‐cell lymphoma
Authors: Sara Ekberg, Mats Jerkeman, Per‐Ola Andersson, Gunilla Enblad, Björn E Wahlin, Sverker Hasselblom, Therese M. Andersson, Sandra Eloranta, Karin E. Smedby
Journal: American Journal of Hematology (2018)

Survival has improved among patients with diffuse large B-cell lymphoma (DLBCL) with the addition of anti-CD20 antibody therapy. We aimed to quantify trends and remaining loss in expectation of life (LEL) due to DLBCL at a national population-based level. Patients diagnosed with DLBCL 2000-2013 (N = 7114) were identified through the Swedish Lymphoma Registry and classified according to the age-adjusted International Prognostic Index (aaIPI). The novel measure LEL is the difference between remaining life years among patients and the general population and was predicted using flexible parametric models from diagnosis and among 2-year survivors, by age and sex. Median age at DLBCL-diagnosis was 70 (18-105) years and 54.8% presented with stage III-IV disease. On average, LEL due to DLBCL decreased from 8.0 (95% CI: 7.7-8.3) to 4.6 (95% CI: 4.5-4.6) years over the study period. By risk group, LEL was most reduced among patients with aaIPI ≥2 aged 50-60 years. However, these patients were still estimated to lose >8 years in 2013 (eg, LEL
Angubindin-1 opens the blood–brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system
Authors: Satoshi Zeniya, Hiroya Kuwahara, Kaiichi Daizo, Akihiro Watari, Masuo Kondoh, Kie Yoshida-Tanaka, Hidetoshi Kaburagi, Ken Asada, Tetsuya Nagata, Masahiro Nagahama, Kiyohito Yagi, Takanori Yokota
Journal: Journal of Controlled Release (2018)

Within the field of RNA therapeutics, antisense oligonucleotide-based therapeutics are a potentially powerful means of treating intractable diseases. However, if these therapeutics are used for the treatment of neurological disorders, safe yet efficient methods of delivering antisense oligonucleotides across the blood-brain barrier to the central nervous system must be developed. Here, we examined the use of angubindin-1, a binder to the tricellular tight junction, to modulate paracellular transport between brain microvascular endothelial cells in the blood-brain barrier for the delivery of antisense oligonucleotides to the central nervous system. This proof-of-concept study demonstrated that intravenously injected angubindin-1 increased the permeability of the blood-brain barrier and enabled transient delivery of subsequently administered antisense oligonucleotides into the mouse brain and spinal cord, leading to silencing of a target RNA without any overt adverse effects. We also found that two bicellular tight junction modulators did not produce such a silencing effect, suggesting that the tricellular tight junction is likely a better target for the delivery of antisense oligonucleotides than the bicellular tight junction. Our delivery strategy of modulating the tricellular tight junction in the blood-brain barrier via angubindin-1 provides a novel avenue of research for the development of antisense oligonucleotide-based therapeutics for the treatment of neurological disorders.
Capping entry visas is creating “massive longstanding” problems, says head of NHS trust
Authors: Matthew Limb
Journal: BMJ (2018)

An NHS trust chief executive has blasted “government foolishness” over refusals of visa applications that threaten to leave hospitals in northwest England short of nearly 100 doctors this summer.

Andrew Foster, head of Wrightington, Wigan and Leigh NHS Foundation Trust, said that unless visa restrictions were lifted they would cause “big holes” in health services immediately. Denying “tier 2” visas to doctors from outside the European Economic Area could also herald “massive longstanding” problems for the NHS because the scheme itself would lose credibility and deter other overseas doctors from applying to work in the UK.

Foster has helped to coordinate a bid to bring around 100 doctors from outside the EEA to work in …
The Affordable Care Act and Adolescents and Young Adults With Cancer
Authors: Peter Hsu, John A. Graves
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 12713: Epidemiology and Mortality of Very and Extremely Preterm Infants With Congenital Heart Defects
Authors: Patricia Y Chu, Jennifer S Li, Andrzej S Kosinski, Christoph P Hornik, Kevin D Hill
Journal: Circulation (2015)

Introduction: Congenital heart disease (CHD) is estimated to occur in 6-10 per 1000 births. Although epidemiology and outcomes for term and near term infants with CHD are well described, data are limited for very and extremely preterm (VEP) infants. We used the Healthcare Cost and Utilization Project Kids’ Inpatient Database (KID), a nationally representative administrative database, to evaluate epidemiology and outcomes for VEP infants (25 to 32 weeks gestational age, GA) with CHD. Methods: Two separate cohorts were defined from the KID: an epidemiologic cohort including birth hospitalizations in ‘03, ’06, ’09 and ‘12; and an outcomes cohort including hospitalizations at a children’s hospital or pediatric unit for infants &lt; 1 month of age in ‘06 and ‘09. CHD was defined by ICD-9-CM codes with severe CHD defined as those defects expected to be universally diagnosed during a preterm birth hospitalization. Weighted multivariate logistic regression analysis was used to calculate odds ratios (OR) for mortality, adjusted for race, sex, GA, year, small for gestational age and hospital teaching status. Results: Our epidemiologic and outcomes cohorts included 249,011 and 49,893 VEP infants, respectively. Incidence of CHD (116/1000 VEP births) and severe CHD (7/1000 VEP births) were both higher than previously reported in term infants. Relative risk of severe CHD in VEP vs term infants was 4.80 (95% CI 4.76, 4.84) and decreased with increasing GA (5.7 at 25 weeks GA to 4.3 at 31 weeks, p=0.005). Hospital mortality (Figure) was substantially higher for VEP infants with vs without severe CHD (26% vs 5%; adjusted OR 7.5 [95% CI: 5.9, 9.6]). Overall 16% of VEP infants with severe CHD underwent cardiac surgery during the neonatal hospitalization with mortality after surgery of 16%. Conclusions: CHD incidence is increased in very and extremely preterm infants and outcomes are poor. These data underscore the need for interventions to decrease preterm delivery when severe CHD is diagnosed in utero.