tbuckley/cabot-search huggingface dataset:
Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model
Authors: Sheetal Trivedi, Satyapramod Murthy, Himanshu Sharma, Alex S. Hartlage, Arvind Kumar, Sashi V. Gadi, Peter Simmonds, Lokendra V. Chauhan, Troels K.H. Scheel, Eva Billerbeck, Peter D. Burbelo, Charles M. Rice, W. Ian Lipkin, Kurt Vandegrift, John M. Cullen, Amit Kapoor
Journal: Hepatology (2017)

The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity, and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus from wild rats (Rattus norvegicus), RHV-rn1; acquired the complete viral genome sequence; and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' untranslated regions. We used site-directed and random mutagenesis to determine that only the first of the two microRNA-122 seed sites in the viral 5' untranslated region is required for viral replication and persistence in rats. Next, we used the clone-derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV-rn1 possesses several HCV-defining hallmarks: hepatotropism, propensity to persist, and the ability to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV-rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct-acting antiviral therapy, sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats.We developed RHV-rn1-infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV-related viral persistence, immunity, and pathogenesis. (Hepatology 2018).
Research Integrity, Academic Promotion, and Attribution of Authorship and Nonauthor Contributions
Authors: Spyros D. Mentzelopoulos, Spyros G. Zakynthinos
Journal: JAMA (2017)

This Viewpoint discusses the importance of research authorship for academic promotion and proposes revision of research integrity codes to define nonauthor contributions and distinguish nonauthor from author contributions to discourage awarding of authorship to nonauthor collaborators.
Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand
Authors: Wouter den Hollander, Cindy G Boer, Deborah J Hart, Michelle S Yau, Yolande F M Ramos, Sarah Metrustry, Linda Broer, Joris Deelen, L Adrienne Cupples, Fernando Rivadeneira, Margreet Kloppenburg, Marjolein Peters, Tim D Spector, Albert Hofman, P Eline Slagboom, Rob G H H Nelissen, André G Uitterlinden, David T Felson, Ana M Valdes, Ingrid Meulenbelt, Joyce J B van Meurs
Journal: Annals of the Rheumatic Diseases (2017)

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10 −10 ) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10 −9 ) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Beta meta =0.83, P meta =1.8*10 −15 ). This variant is high linkage disequilibrium with a coding variant in MGP , a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p&lt;5*10 −16 ). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP , which may increase the burden of hand OA by decreased inhibition of cartilage calcification.
Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis
Authors: Naoto Koyanagi, Takahiko Imai, Keiko Shindo, Ayuko Sato, Wataru Fujii, Takeshi Ichinohe, Naoki Takemura, Shigeru Kakuta, Satoshi Uematsu, Hiroshi Kiyono, Yuhei Maruzuru, Jun Arii, Akihisa Kato, Yasushi Kawaguchi
Journal: Journal of Clinical Investigation (2017)

Herpes simplex virus-1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1-specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1-specific CD8+ T cell accumulation in infection sites by downregulating expression of the CD8+ T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1-specific CD8+ T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of CD8+ T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis.
Natural Selection Drives Rapid Functional Evolution of Young Drosophila Duplicate Genes
Authors: Xueyuan Jiang, Raquel Assis
Journal: Molecular Biology and Evolution (2017)

Gene duplication is thought to play a major role in phenotypic evolution. Yet the forces involved in the functional divergence of young duplicate genes remain unclear. Here, we use population-genetic inference to elucidate the role of natural selection in the functional evolution of young duplicate genes in Drosophila melanogaster. We find that negative selection acts on young duplicates with ancestral functions, and positive selection on those with novel functions, suggesting that natural selection may determine whether and how young duplicate genes are retained. Moreover, evidence of natural selection is strongest in protein-coding regions and 3' UTRs of young duplicates, indicating that selection may primarily target encoded proteins and regulatory sequences specific to 3' UTRs. Further analysis reveals that natural selection acts immediately after duplication and weakens over time, possibly explaining the observed bias toward the acquisition of new functions by young, rather than old, duplicate gene copies. Last, we find an enrichment of testis-related functions in young duplicates that underwent recent positive selection, but not in young duplicates that did not undergo recent positive selection, or in old duplicates that either did or did not undergo recent positive selection. Thus, our findings reveal that natural selection is a key player in the functional evolution of young duplicate genes, acts rapidly and in a region-specific manner, and may underlie the origin of novel testis-specific phenotypes in Drosophila.
MRI for Neonates
Authors: Rebecca Voelker
Journal: JAMA (2017)

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Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection
Authors: Hidenori Toyoda, Kazuaki Chayama, Fumitaka Suzuki, Ken Sato, Tomofumi Atarashi, Tsunamasa Watanabe, Masanori Atsukawa, Atsushi Naganuma, Kazuo Notsumata, Yukio Osaki, Makoto Nakamuta, Koichi Takaguchi, Satoru Saito, Koji Kato, David Pugatch, Margaret Burroughs, Rebecca Redman, Katia Alves, Tami J. Pilot‐Matias, Rajneet K. Oberoi, Bo Fu, Hiromitsu Kumada
Journal: Hepatology (2017)

Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once‐daily, all oral, ribavirin (RBV)‐free, direct‐acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)–infected Japanese patients, including those with compensated cirrhosis. CERTAIN‐2 is a phase 3, open‐label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment‐naive and interferon ± RBV treatment–experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600‐1000 mg weight‐based, twice daily) (arm B). The primary endpoint was noninferiority of G/P compared to sofosbuvir + RBV by assessing sustained virologic response at posttreatment week 12 (SVR12) among patients in the intent‐to‐treat population. SVR12 was also assessed in treatment‐naive and interferon ± RBV treatment‐experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the CERTAIN‐1 study. A total of 136 patients were enrolled in CERTAIN‐2. SVR12 was achieved by 88/90 (97.8%) patients in arm A and 43/46 (93.5%) patients in arm B. No patient in arm A experienced virologic failure, while 2 did in arm B. The primary endpoint was achieved. In CERTAIN‐1, 100% (18/18) of GT2‐infected patients with compensated cirrhosis achieved SVR12. Treatment‐emergent serious adverse events were experienced by 2 patients without cirrhosis in each arm and no patient with cirrhosis. Conclusion: The results demonstrate high efficacy and favorable tolerability of G/P in GT2‐infected Japanese patients. (H epatology 2018;67:505‐513).
European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative
Authors: Noortje Groot, Nienke de Graeff, Stephen D Marks, Paul Brogan, Tadej Avcin, Brigitte Bader-Meunier, Pavla Dolezalova, Brian M Feldman, Isabelle Kone-Paut, Pekka Lahdenne, Liza McCann, Seza Özen, Clarissa A Pilkington, Angelo Ravelli, Annet van Royen-Kerkhof, Yosef Uziel, Bas J Vastert, Nico M Wulffraat, Michael W Beresford, Sylvia Kamphuis
Journal: Annals of the Rheumatic Diseases (2017)

Lupus nephritis (LN) occurs in 50%–60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high-quality care for all children with SLE.
Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials
Authors: Howard L. Kaufman, Robert H. I. Andtbacka, Frances A. Collichio, Michael Wolf, Zhongyun Zhao, Mark Shilkrut, Igor Puzanov, Merrick Ross
Journal: Journal for ImmunoTherapy of Cancer (2017)

Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival.We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation).Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025).Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint.ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.
YOCAS yoga, fatigue, memory difficulty, and quality of life: Results from a URCC CCOP randomized, controlled clinical trial among 358 cancer survivors.
Authors: Michelle Christine Janelsins, Luke Joseph Peppone, Charles E Heckler, Lisa Sprod, Supriya Gupta Mohile, Kavita Dayal Chandwani, Jeffrey J. Kirshner, Pavan S. Reddy, Gary R. Morrow, Karen Michelle Mustian
Journal: Journal of Clinical Oncology (2012)

9142 Background: Memory difficulty is a serious problem for many cancer survivors and can negatively affect quality of life (QOL). Little evidence exists on the effects of physical activity (PA) interventions, such as yoga, on memory in cancer survivors. We previously reported in a nationwide, Phase III RCT that YOCAS Yoga, implemented over 4 weeks (2 x/wk; 75 min/session), significantly improved fatigue and QOL in cancer survivors. The purpose of this study was to assess the effects of YOCAS on memory and to identify moderating and possible mediating effects of memory in YOCAS improvements of fatigue and QOL. Methods: Cancer survivors between 2-24 months post adjuvant therapy with no participation in yoga during the previous 3 months were randomized to standard care (SC) or SC with YOCAS. YOCAS consists of breathing exercises, gentle Hatha and Restorative yoga postures and meditation. This secondary analysis included participants (N=358, mean age = 54, 96% female, 75% breast cancer) who provided pre- and post-intervention data on Difficulty Remembering Things (modified MD Anderson Symptom Inventory with 0 = “Did not Interfere” to 10 = “Interfered Completely”), fatigue and QOL (FACIT-F). ANCOVA was used to assess the effects of YOCAS on memory at post-intervention incorporating baseline memory score. Path Modeling was conducted to assess the moderating and mediating effects of memory on YOCAS changes in fatigue and QOL. Results: ANCOVA revealed a significant group effect of YOCAS on memory at post intervention (mean change: Yoga - Control = -0.44; Cohen’s D= -0.24; p &lt;0.05). Moderation analyses revealed that baseline memory difficulty did not affect how much YOCAS would improve fatigue (p&gt;0.05) or QOL (p&gt;0.05). Mediation analyses identified changes in memory as a significant partial mediator for improved fatigue (p&lt;0.05) and improved QOL (p&lt;0.05). Conclusions: YOCAS yoga significantly reduces perceived memory difficulty in cancer survivors. Improvements in memory due to YOCAS may be a possible mediator for improving fatigue and QOL. More elaborate PA RCTs are needed to confirm these results. Funding: NCIR25CA10618, K07CA120025, and U10CA37420.
Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study
Authors: Xiaoqin Liu, Esben Agerbo, Katja G Ingstrup, Katherine Musliner, Samantha Meltzer-Brody, Veerle Bergink, Trine Munk-Olsen
Journal: BMJ (2017)

Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.Design Population based cohort study.Setting Danish national registers.Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk.Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer
Authors: J.H. Chung, D. Pavlick, R. Hartmaier, A.B. Schrock, L. Young, B. Forcier, P. Ye, M.K. Levin, M. Goldberg, H. Burris, L.M. Gay, A.D. Hoffman, P.J. Stephens, G.M. Frampton, D.M. Lipson, D.M. Nguyen, S. Ganesan, B.H. Park, L.T. Vahdat, B. Leyland-Jones, T.I. Mughal, L. Pusztai, J. O’Shaughnessy, V.A. Miller, J.S. Ross, S.M. Ali
Journal: Annals of Oncology (2017)

Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.
Using information technology to improve surveillance of antimicrobial resistance in South East Asia
Authors: Sirenda Vong, Amaury Anciaux, Anette Hulth, John Stelling, Visanu Thamlikitkul, Sunil Gupta, Jonas M Fuks, Kāmini Walia, Pinyo Rattanumpawan, Sergey Eremin, Klara Tisocki, Tika R Sedai, Anuj Sharma
Journal: BMJ (2017)

<b>Sirenda Vong and colleagues</b> argue that investing in information technology surveillance systems to detect trends is an essential first step in tackling antimicrobial resistance in South East Asian countries
Frederick Brian Cookson
Authors: Bill Foster
Journal: BMJ (2017)

Frederick Brian Cookson (“Brian”) was born in Stourbridge and grew up in a family in which there was always music. Brian’s interests and talents were wide in science and the arts, especially poetry, piano, and singing. He chose to study natural sciences at St. John’s College, Cambridge, with clinical years in Birmingham. After qualifying in 1961, his initial jobs were in Birmingham hospitals, and it was here he met and married Hilary, a radiographer.

Brian cared passionately about medicine. For a man with such broad interests in science, the humanities, and people, it soon became clear that general practice was the place to be. After working initially in Gloucester as an assistant, he was a partner in a practice in Bicester for four years. He then moved back to Gloucester with his growing family, when a partnership became available. Brian was always …