tbuckley/cabot-search huggingface dataset:
Neutral Theory, Disease Mutations, and Personal Exomes
Authors: Sudhir Kumar, Ravi Patel
Journal: Molecular Biology and Evolution (2018)

Genetic differences between species and within populations are two sides of the same coin under the neutral theory of molecular evolution. This theory posits that a vast majority of evolutionary substitutions, which appear as differences between species, are (nearly) neutral, that is, these substitutions are permitted without a significantly adverse impact on a species' survival. We refer to them as evolutionarily permissible (ePerm) variation. Evolutionary permissibility of any possible variant can be inferred from multispecies sequence alignments by applying sophisticated statistical methods to the evolutionary tree of species. Here, we explore the evolutionary permissibility of amino acid variants associated with genetic diseases and those observed in personal exomes. Consistent with the predictions of the neutral theory, disease associated amino acid variants are rarely ePerm, much more biochemically radical, and found predominantly at more conserved positions than their non-disease counterparts. Only 10% of amino acid mutations are ePerm, but these variants rise to become two-thirds of all substitutions in the human lineage (a 6-fold enrichment). In contrast, only a minority of the variants in a personal exome are ePerm, a seemingly counterintuitive pattern that results from a combination of mutational and evolutionary processes that are, in fact, broadly consistent with the neutral theory. Evolutionarily forbidden variants outnumber detrimental variants in individual exomes and may play an underappreciated role in protecting against disease. We discuss these observations and conclude that the long-term evolutionary history of species can illuminate functional biomedical properties of variation present in personal exomes.
Defining the characteristics of certified hernia centers in Italy: The Italian society of hernia and abdominal wall surgery workgroup consensus on systematic reviews of the best available evidences
Authors: Cesare Stabilini, Giuseppe Cavallaro, Paolo Bocchi, Giampiero Campanelli, Michele Carlucci, Francesca Ceci, Feliciano Crovella, Diego Cuccurullo, Landino Fei, Ezio Gianetta, Francesco Gossetti, Dalila Patrizia Greco, Olga Iorio, Pierluigi Ipponi, Antonio Marioni, Giovanni Merola, Paolo Negro, Denise Palombo, Umberto Bracale
Journal: International Journal of Surgery (2018)
Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex
Authors: Sirui Jiang, Priya Nandy, Wenzhang Wang, Xiaopin Ma, Jeffrey Hsia, Chunyu Wang, Zhenlian Wang, Mengyue Niu, Sandra L. Siedlak, Sandy Torres, Hisashi Fujioka, Ying Xu, Hyoung-gon Lee, George Perry, Jun Liu, Xiongwei Zhu
Journal: Molecular Neurodegeneration (2018)

Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease. To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD. Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size. Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.
Performance and reliability of non-invasive fibrosis scores in nonalcoholic fatty liver disease with and without morbid obesity
Authors: A. Drolz, S. Wolter, M. Wehmeyer, F. Piecha, T. Horvatits, J.S.Z. Wiesch, A. Lohse, O. Mann, J. Kluwe
Journal: Journal of Hepatology (2018)
Distribution and changes of FIB-4 index in normal health checkup examinees
Authors: S. Hige, I. Ozeki, J. Akaike, R. Tatsumi, M. Yamaguchi, M. Kimura, T. Arakawa, T. Nakajima, Y. Kuwata, T. Ohmura, J. Toyota, Y. Karino
Journal: Journal of Hepatology (2018)
Progression of Multiple Myeloma Detected on Cardiac Scintigraphy with 99mTc Sestamibi
Authors: Jonathan Bulzan, Jonathan Revels, Kathy Byun
Journal: Clinical Nuclear Medicine (2018)

It is important to understand normal and abnormal radiotracer biodistribution patterns in patients who undergo cardiac Tc-2-methoxyisobutyl-isonitrile (Tc-sestamibi) scans to provide important clinical guidance. Our case describes a 75-year-old man with a history of multiple myeloma in remission, who presented to the emergency department for unrelated chest pain and shortness of breath. The patient underwent a nuclear cardiac stress test with Tc-sestamibi scintigraphy as part of his cardiac workup. The images demonstrated diffuse radiotracer uptake in the skeletal structures raising concern for progression of multiple myeloma, of which, subsequent biopsy confirmed the presence of recurrent disease.
Long-term outcome of hepatitis delta compared to HBV monoinfection
Authors: A. Wranke, K. Deterding, B. Heidrich, B.C. Serrano, J. Kirschner, B. Bremer, C. Mix, K. Port, M. Cornberg, M.P. Manns, H. Wedemeyer
Journal: Journal of Hepatology (2018)
New evidence challenges use of bath emollients for children with eczema
Authors: Carsten Flohr, Amina Ahmed
Journal: BMJ (2018)

SUMMARY  In combination with advanced mechanistic modeling and the generation of high-quality multi-dimensional data sets, machine learning is becoming an integral part of understanding and engineering living systems. Here we show that mechanistic and machine learning models can complement each other and be used in a combined approach to enable accurate genotype-to-phenotype predictions. We use a genome-scale model to pinpoint engineering targets and produce a large combinatorial library of metabolic pathway designs with different promoters which, once phenotyped, provide the basis for machine learning algorithms to be trained and used for new design recommendations. The approach enables successful forward engineering of aromatic amino acid metabolism in yeast, with the new recommended designs improving tryptophan production by up to 17% compared to the best designs used for algorithm training, and ultimately producing a total increase of 106% in tryptophan accumulation compared to optimized reference designs. Based on a single high-throughput data-generation iteration, this study highlights the power of combining mechanistic and machine learning models to enhance their predictive power and effectively direct metabolic engineering efforts.
Functional Brain Networks Are Dominated by Stable Group and Individual Factors, Not Cognitive or Daily Variation
Authors: Caterina Gratton, Timothy O. Laumann, Ashley N. Nielsen, Deanna J. Greene, Evan M. Gordon, Adrian W. Gilmore, Steven M. Nelson, Rebecca S. Coalson, Abraham Z. Snyder, Bradley L. Schlaggar, Nico U.F. Dosenbach, Steven E. Petersen
Journal: Neuron (2018)
Reducing Surgical Resident Attrition
Authors: Christiana Shaw, George A. Sarosi
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
Transient elastography for screening of liver fibrosis in the population: A cost-effectiveness analysis using prospective databases from 6 countries in Europe and Asia
Authors: M. Serra, I. Graupera, L. Caballeria, M. Thiele, D. Roulot, W.S.V. Wong, N. Guha, N. Fabrellas, F. Lammert, R. Hernández, L.-H.G. Wong, A. Juanola, S.D. Murad, A. Krag, P. Angeli, P. Galle, P. Torán, C. Laurent, P. Ginès
Journal: Journal of Hepatology (2018)
1-Year Outcomes of Transcatheter Mitral Valve Replacement in Patients With Severe Mitral Annular Calcification
Authors: Mayra Guerrero, Marina Urena, Dominique Himbert, Dee Dee Wang, Mackram Eleid, Susheel Kodali, Isaac George, Tarun Chakravarty, Moses Mathur, David Holzhey, Ashish Pershad, H. Kenith Fang, Daniel O’Hair, Noah Jones, Vaikom S. Mahadevan, Nicolas Dumonteil, Josep Rodés-Cabau, Nicolo Piazza, Enrico Ferrari, Daniel Ciaburri, Mohammed Nejjari, Augustin DeLago, Paul Sorajja, Firas Zahr, Vivek Rajagopal, Brian Whisenant, Pinak Bipin Shah, Jan-Malte Sinning, Adam Witkowski, Helene Eltchaninoff, Danny Dvir, Bena Martin, Guilherme F. Attizzani, Diego Gaia, Nagela S.V. Nunes, Amir-Ali Fassa, Faraz Kerendi, Gregory Pavlides, Vijay Iyer, Georges Kaddissi, Christian Witzke, James Wudel, Gregory Mishkel, Bryan Raybuck, Chi Wang, Ron Waksman, Igor Palacios, Alain Cribier, John Webb, Vinnie Bapat, Mark Reisman, Raj Makkar, Martin Leon, Charanjit Rihal, Alec Vahanian, William O’Neill, Ted Feldman
Journal: Journal of the American College of Cardiology (2018)
Correction: Distributional change of women’s adult height in low- and middle-income countries over the past half century: An observational study using cross-sectional survey data
Authors: Jewel Gausman, Iván Mejía-Guevara, S. V. Subramanian, Fahad Razak
Journal: PLoS Medicine (2018)

[This corrects the article DOI: 10.1371/journal.pmed.1002568.].
NHS waiting times: number of patients waiting 18 weeks for treatment rises sharply
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The number of people waiting more than 18 weeks for NHS treatment has increased by 35% in the past year, official figures show.1

Performance data from NHS England also showed that 25 475 operations were cancelled at the last minute in January-March 2018. The Royal College of Surgeons noted that this was the highest number since quarterly records began in 1994.

The college said that “extreme pressures” in emergency departments had affected waiting times for planned surgery. In January, NHS England advised hospitals to defer non-urgent surgery until the end …
Outcomes and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcoma metastatic to the spine.
Authors: Michael Ryan Folkert, Mark Bilsky, Ashlyn K. Tom, Kaled M. Alektiar, Ilya Laufer, William D. Tap, Yoshiya Yamada
Journal: Journal of Clinical Oncology (2013)

9501 Background: Conventional radiation treatment (20-40 Gy total dose, 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses and results in poor local control (58-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of control and salvage for these lesions. Methods: Patients with pathologically-proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. Local control (LC) and overall survival (OS) were analyzed using Kaplan-Meier statistics; univariate/multivariate analyses were performed using Cox regression. Toxicities were assessed according to CTCAE v4.0 criteria. Results: From 5/2005 and 11/2012, 88 patients with 120 discrete metastases were treated with HF (3-6 fractions, median dose 28.5 Gy; n=52, 43.3%) or SF IG-SRS (median dose 24 Gy, n=68, 56.7%). Median followup was 12.3 months. LC at 12 months was 87.9% (95% CI 81.3-94.5%). OS at 12 months was 60.6% (95% CI 49.6-71.6%) with a median survival of 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (P=.007) (Table). SF IG-SRS retained its significance in terms of improved LC on multivariate analysis, HR 0.304 (95% CI: 0.117-0.790); variables tested included prior radiation therapy, histology, IG-SRS fractionation, surgery, and chemotherapy. Treatment was well-tolerated with 1% acute Grade 3 toxicity and 4.5% chronic Grade 3 toxicity observed; there were no &gt; Grade 3 toxicities. Conclusions: In the largest series of metastatic sarcoma to the spine to date, image-guided stereotactic radiosurgery provides excellent local control in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction image-guided stereotactic radiosurgery demonstrates the highest rates of local control with minimal toxicity. [Table: see text]
A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer
Authors: Johanna C. Bendell, Anna M. Varghese, David M. Hyman, Todd M. Bauer, Shubham Pant, Sophie Callies, Ji Lin, Ricardo Martinez, Enaksha Wickremsinhe, Aaron Fink, Volker Wacheck, Kathleen N. Moore
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. Patients and Methods: A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. Clin Cancer Res; 24(14); 3253–62. ©2018 AACR.
41Does human epicardial adipose tissue enhance atrial fibrillation induced by beta adrenergic stimulation in human cardiac muscles?
Authors: A A Babakr, I C Fomison-Nurse, P P Jones, R R Lamberts
Journal: Cardiovascular Research (2018)

Background: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia.Beta (b)adrenergic stimulation is a well-known trigger of AF.Excessive epicardial adipose tissue (EAT) around the heart is also a risk factor for AF.However, whether b-adrenergic activation stimulates EAT to promote AF in human myocardium remains unknown.Purpose: To determine if human EAT enhances AF induced by b-adrenergic stimulation in human atrial muscles.Methods: After informed consent, human right atrial appendages were obtained from patients that underwent open chest surgery (n ¼ 20).From the tissue isolated muscles (trabeculae) were mounted in a bath, and the susceptibility of AF was measured based on the development of spontaneous contractions during one-minute rest period that followed one-minute stimulation at 1Hz (60 bpm) (automaticity protocol).The automaticity protocol was then repeated following 30 minutes of b-adrenergic stimulation (isoproterenol (ISO), 10-5M).In a separate group of patients (n ¼ 10), trabeculae and a piece of human EAT (average weight ¼ 53 6 8 mg) was obtained.The EAT was situated upstream of the muscle in an adjacent bath, so the superfusion fluid of the EAT flows over the trabecula, and the automaticity protocol was performed during b-adrenergic stimulation (ISO, 10-5M) in the absence and presence of EAT in the adjacent bath.Results: b-adrenergic stimulation increased the percentage of muscles with spontaneous contractions (No ISO: 0%, with ISO: 55%, p < 0.001, Chi-square test) and also the numbers of spontaneous contraction (No ISO: 0 vs. with ISO: 2267 number of spontaneous contractions, p¼0.001,Wilcoxon signed-rank test).In the second group, superfusion of the muscles with EAT alone did not induce spontaneous contractions in the muscles.Interestingly, when the EAT was triggered by b-adrenergic stimulation, 70% of the muscles superfused with EAT developed spontaneous contractions compared to 20% of the muscles without EAT superfusion (p¼0.02,Chi-square test).However, there was no significant difference in the numbers of spontaneous contractions between the muscles superfused with or without EAT after b-adrenergic stimulation (No EAT: 12610 vs. with EAT 1468, number of spontaneous contractions, p¼0.2, Wilcoxon signed-rank test). Conclusion:The b-adrenergic stimulation-induced increases in the susceptibility for developing spontaneous contractions in human cardiac muscles was enhanced in the presence of human EAT.Thus, human EAT has a functional interaction with the human myocardium that affects the susceptibility for AF, specifically through modulation of the b-adrenergic arrhythmogenic trigger.
Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1
Authors: Ik-Jung Kim, Jeongmin Lee, Seung J. Oh, Mee-Sup Yoon, Sung-Soo Jang, Robin L. Holland, Michael L. Reno, Mohammed N. Hamad, Tatsuya Maeda, Hee Jung Chung, Jie Chen, Steven R. Blanke
Journal: Cell Host & Microbe (2018)
The Role of Pediatricians in Reproductive Health Advocacy
Authors: Tracey A. Wilkinson, Aaron E. Carroll
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
Atopic asthma after rhinovirus‐induced wheezing is associated with <scp>DNA</scp> methylation change in the <i><scp>SMAD</scp>3</i> gene promoter
Authors: R. J. Lund, M. Osmala, M. Malonzo, M. Lukkarinen, A. Leino, J. Salmi, S. Vuorikoski, R. Turunen, T. Vuorinen, C. Akdis, H. Lähdesmäki, R. Lahesmaa, T. Jartti
Journal: Allergy (2018)

Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic asthma, we analyzed a cohort of 5-year-old children (n = 45) according to the virus etiology of the first severe wheezing episode at the mean age of 13 months and to 5-year asthma outcome. The development of atopic asthma in children with early rhinovirus-induced wheezing was associated with DNA methylation changes at several genomic sites in chromosomal regions previously linked to asthma. The strongest changes in atopic asthma were detected in the promoter region of SMAD3 gene at chr 15q22.33 and introns of DDO/METTL24 genes at 6q21. These changes were validated to be present also at the average age of 8 years.
Do direct acting antivirals cure chronic hepatitis C?
Authors: Janus Christian Jakobsen, Emil Eik Nielsen, Ronald L Koretz, Christian Gluud
Journal: BMJ (2018)

What you need to know• Direct acting antivirals (DAAs) are relatively expensive drugs that have been promoted as a cure for chronic hepatitis C• There is insufficient evidence to judge if DAAs reduce mortality or other liver related complications from chronic hepatitis C• Discuss with your patient the uncertain clinical benefit, and the risks and costs of these drugs, to make a shared decision on treatment
Reply to the comments on: concurrent aerobic plus resistance exercise versus aerobic exercise alone to improve health outcomes in paediatric obesity: a systematic review and meta-analysis
Authors: Antonio García-Hermoso, Robinson Ramírez-Vélez, Rodrigo Ramírez-Campillo, Mark D Peterson, Vicente Martínez-Vizcaíno
Journal: British Journal of Sports Medicine (2018)

Dear Editor,

We appreciate the interest in our recent meta-analysis1 and welcome the opportunity to reply.2

First, with regard to methodological quality of the studies included in our systematic review, we totally agree with the comment regarding the need for a specific tool to evaluate the risk of bias in non-randomised intervention studies. Despite the low quality, no trials were excluded according to this quality. In our meta-analysis, we chose to include all studies and to …
Direct-acting antiviral treatment in sub-Saharan Africa: A prospective trial of Ledipasvir/Sofosbuvir for chronic Hepatitis C infection in Rwanda (the SHARED study)
Authors: N. Gupta, J. Kabahizi, C. Muvunyi, A. Mbituyumuremyi, J. Van Nuil, F. Shumbusho, F. Ntaganda, M.J. Damascene, C. Mukabatsinda, E. Musabeyezu, C. Ntirenganya, S. Nsanzimana, P. Grant
Journal: Journal of Hepatology (2018)