tbuckley/cabot-search huggingface dataset:
HEVnet: a One Health, collaborative, interdisciplinary network and sequence data repository for enhanced hepatitis E virus molecular typing, characterisation and epidemiological investigations
Authors: Annemieke Christine Mulder, Annelies Kroneman, Eelco Franz, Harry Vennema, Anna D. Tulen, Johanna Takkinen, Agnetha Hofhuis, Cornelia Adlhoch
Journal: Eurosurveillance (2019)

Hepatitis E virus (HEV) is a common cause of acute hepatitis worldwide. In Europe, HEV is a zoonosis transmitted via contaminated pork meat or other pork food products. Genotype 3 is the most prevalent HEV type in the animal reservoir, as well as in humans. Despite an increased incidence of hepatitis E across Europe, much remains unknown about its spread, sources and transmission routes. A One Health approach is crucial to better understand the (molecular) epidemiology of HEV. HEVnet was established in April 2017 as a network and database for sharing sequences and accompanying metadata collected from human, animal, food and environmental sources. HEVnet members working in the public health, veterinary health, food, environmental and blood safety sectors have submitted 1,615 HEV sequences from nine countries as at January 2019. Most are from humans (89%), and sequences of animal (5%), food (6%) or environmental (0.3%) origin are rare. Metadata for human sequences capture mostly sex (93%), year of birth (92%) and sampling (100%); data on region of sampling (37%) and clinical information (hospitalisation 27%, symptoms 20% or mortality 8%) are limited. HEVnet aims to expand into a global network capable of performing cross-sectoral and supranational studies, with a joint repository of molecular and epidemiological data on HEV.
Employing head and neck cancer patient derived xenografts to inform clinical trial design: Results from combining regorafenib with everolimus.
Authors: Konrad Friedrich Klinghammer, Jan D Raguse, Andreas Albers, Annika Wulf-Goldenberg, Dieter Zopf, Jens Hoffmann, Iduna Fichtner, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2015)

e17034 Background: We recently established a panel of 65 head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDX) for exploration of novel treatment approaches and biomarker evaluation. Up to date neither inhibition of neo-angiogenesis nor mTOR inhibition is an established treatment option for HNSCC. We therefore evaluated the response to single agent and combinational treatment of regorafenib and everolimus. Methods: 17 different HNSCC PDX were treated with regorafenib (10 mg/kg/d) and everolimus (4 mg/kg/d) as single agent. Since response to single agents was moderate combined treatment was evaluated consecutively in six models. Response was determined by comparing tumor volume at the beginning to the end of treatment (RTV). A RTV between 0.8-1.2 was considered stable disease, values above 1.2 as progressive disease and below as partial response. Further, treatment response was correlated to mutational profile. Results: Regorafenib treatment resulted in one partial remission and one stable disease within the 17 models. Best result for single agent treatment of regorafenib was seen in a model harbouring VEGFR2 and RET mutation. Response to treatment with single agent everolimus resulted in stable disease in 3 out of 17 models. Combining the two treatments resulted in stable disease in 5 of 6 models during the treatment period of two weeks. Body weight remained stable under single agent and combined treatment, suggesting that the treatments were well tolerated. Conclusions: By employing head and neck cancer patient derived xenografts we created a rationale for evaluating regorafenib in combination with everolimus in head and neck cancer within a clinical setting. Biomarker studies for treatment response to potentially stratify patients in a subsequent clinical trial are ongoing. PDX ID RTV combined treatment response 11142 0.91 stable disease 11841 1.19 stable disease 11857 1.66 progressive disease 10883 0.91 stable disease 11143 1.14 stable disease 11527 1.04 stable disease
GMC chair calls for more frontline consultant presence in hospitals
Authors: Abi Rimmer
Journal: BMJ (2019)

The newly appointed chair of the General Medical Council has called on senior doctors to provide visible frontline leadership in hospital wards and to call out examples of poor practice where necessary.

In a speech at the Royal College of Physicians and Surgeons of Glasgow on Thursday 7 March Clare Marx highlighted research showing that having consultant surgeons present on wards improved patients’ mortality rates by 33%.1

“There is something we could do, within the resource that we already have, that could potentially …
Abstract 16429: Neuro-endocrino-immunological PBMC Signatures Early After Mechanical Support Device Implantation
Authors: Charlotte Starling, Martin Cadeiras, Eleanor Chang, Galyna Bondar, Nicholas Wisniewski, Maral Bakir, Andrew Shubov, Wei Zhou, David Liem, Mario Deng
Journal: Circulation (2015)

Background: The neuro-endocrino-immunological (NEI) pathophysiology associated with advanced heart failure (AdHF) progression and arrythmogenesis is not well understood. While it has been shown that mechanical circulatory support device (MCSD) implantation rapidly restores normal hemodynamics, it is unknown as to whether NEI mechanisms also normalize rapidly. We hypothesized that transcriptional activity in PBMC reflecting NEI normalizes shortly after MCSD implantation. Methods: We collected PBMC samples from 25 MCSD patients and 4 healthy controls (CTRL). Samples were obtained at 1 day before, and 1, 3, 5 and 8 days after MCSD. Purified mRNA was subjected to whole-genome NGS analysis. Statistically significant genes, dysregulated between AdHF patients and CTRLs, were subjected to time dependent bioinformatics analysis. Results: We identified 1226 dysregulated gene-transcripts between AdHF patients and CRTLs at baseline. Time dependent analysis provided 344 dysregulated transcripts in AdHF patients across all time-points. An analysis of enriched molecular pathways by dysregulated genes showed 52 pathways with NEI annotations at baseline. The Endothelin pathway, one of the most significant of the 52 pathways, had 17/60 dysregulated transcripts in AdHF patients at baseline and through day 8 after implantation (Fig.1A). Within the Endothelin pathway we found that expression of EDNRB, a gene central to ET1 clearance and ECE-inhibition, is persistently elevated through day 8 after MCSD (Fig.1B). Conclusion: Transcriptional NEI dysregulation is persistent in PBMC 8 days after MCSD implantation. Neuromodulatory strategies targeted at NEI dysregulation and implemented after MCSD implantation may be a mechanism to improve perioperative outcomes. Further studies including validation methods to objectively assess NEI activity are warranted.
A NEW THERAPY FOR NONALCOHOLIC FATTY LIVER DISEASE AND DIABETES? INT-747-THE FIRST FXR HEPATIC THERAPEUTIC STUDY
Authors: AJ Sanyal, S Mudaliar, RR Henry, HU Marschall, L Morrow, CI Sciacca, P Dillon, P Clopton, M Kipnes, D Shapiro
Journal: Hepatology (2009)
Abstract 16492: Excessive Supraventricular Ectopic Activity and Cognitive Function: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Mary R Rooney, Faye L Norby, Ryan J Koene, Ankit Maheshwari, Pamela L Lutsey, Elsayed Z Soliman, Laura R Loehr, Thomas H Mosley, Josef Coresh, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2017)

Introduction: Supraventricular ectopic beats (SVE) are common and considered benign. However, excessive supraventricular ectopy activity (ESVEA) has been associated with incident atrial fibrillatio...
Abstract P339: 30-Year Absolute Risks for Coronary Heart Disease in Individuals With Very Low LDL-C
Authors: William Schultz, Hongyan Ning, Amanda Marma-Perak, Matthew Feinstein, Allan Sniderman, Jennifer Robinson, Jarett Berry, Donald M Lloyd-Jones, John T Wilkins
Journal: Circulation (2019)

Introduction: It is unclear if individuals with very low mean low-density lipoprotein cholesterol (LDL-C) during midlife experience significant absolute risk (AR) for coronary heart disease (CHD). Hypothesis: Individuals with LDL-C ≤80mg/dL from ages 20-60 years (y) do not develop significant AR for CHD over 30 y of follow-up. Methods: Our objective was to quantify and compare the 30-year AR for fatal or nonfatal CHD from index ages 20-40 y and 40-60 y in participants (ppts) with LDL-C ≤80, 81-130, and &gt;130 mg/dL using data from the Lifetime Risk Pooling Project. We included ppts who were free from lipid lowering medications and CHD at baseline. Mean LDL-C was an average of multiple (2-5) fasting LDL-C measurements within 10 years prior to the baseline age. We used a modified Kaplan Meier analysis, adjusted for competing risks of death, to quantify the 30-year CHD AR by LDL-C strata. Results: 3,781 men and 4,995 women were followed for a combined 110,431 person*years and experienced 778 events. Among all ppts, tobacco use ranged from 20-40% and hypertension prevalence ranged from 13-40%. Non-lipid risk factor profiles were generally more favorable in the low-LDL-C strata. At index ages 20-40, men and women with LDL-C ≤80mg/dL did not experience risk for CHD over 20 and 25 years, respectively (Figure). A similar pattern was seen in the LDL-C 80-130mg/dL strata. At index ages 40-60, men and women with LDL-C ≤80mg/dL experienced no risk for CHD for 5 to 15 years, respectively. However, both sex groups saw a gradual increase in risk up to 13.7% (95% confidence interval [CI] 1.9-25.4%) for men and 5.2% (95% CI 2.0-8.4%) for women at year 30 of follow-up. Conclusion: Young ppts with LDL-C ≤80mg/dL had very low CHD risks across midlife despite significant risk factor burden. At older ages, ppts with low LDL-C develop modest AR for CHD suggesting adverse lipid changes over time or alternative mediators of CHD in this age group.
Asian Subgroup Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study
Authors: Chang-Ki Min, Sung-Soo Yoon, Wee Joo Chng, Shang-Yi Huang, Cheng-Shyong Chang, Raymond Siu Ming Wong, Kazuyuki Shimizu, Nan Gao, Anthony Glennane, Xuesong Guan
Journal: Blood (2018)
Classical Empiric Antifungal Therapy Vs. D-Index Guided Early Therapy Using Micafungin for Persistent Febrile Neutropenia (CEDMIC trial): A Randomized Controlled Trial from Japan FN Study Group
Authors: Shun-Ichi Kimura, Yoshinobu Kanda, Masaki Iino, Takahiro Fukuda, Emiko Sakaida, Tatsuo Oyake, Hiroki Yamaguchi, Shin-ichiro Fujiwara, Junji Suzumiya, Akinao Okamoto, Hiroyuki Fujita, Yasushi Takamatsu, Yoshio Saburi, Jun Yamanouchi, Itaru Matsumura, Souichi Shiratori, Moritaka Gotoh, Shingen Nakamura, Kazuo Tamura
Journal: Blood (2018)
Do elderly men (&gt;75) harbor more aggressive prostate cancer? Comparison of decipher and PAM50 TESTS among different age groups.
Authors: Hanan Goldberg, Jaime Omar Herrera Cáceres, Maria Santiago-Jimenez, Nicholas Fishbane, Elai Davicioni, Zachary William Abraham Klaassen, Thenappan Chandrasekar, Christopher Wallis, Teck Sing Woon, Robert James Hamilton, Girish S. Kulkarni, Alejandro Berlin, Neil Eric Fleshner
Journal: Journal of Clinical Oncology (2019)

38 Background: Age is an important prognostic factor in oncology. Over 20% of men diagnosed with prostate cancer (PC) are ≥ 75 years old. In the growing elderly population, objective methods for predicting outcomes beyond chronologic age are necessary in order minimize the likelihood of withholding curative treatment when warranted. Herein, we describe and analyze age-related differences in clinico-genomic prognostic indices of aggressiveness in localized PC. Methods: Clinical and genomic data for 8,355 patients from the Decipher Genomic Resource Information Database was obtained. Conventional and genomic prognostic indices including Decipher GC scores, PAM50 molecular subtypes (e.g. luminal A/B or basal) NCCN risk groups and Gleason groups (GG) were stratified by age using multivariable logistic regression analyses (MLRA). Results: With increasing decile of age, we observed a higher proportion of high GG and higher Decipher scores. There was a statistically significant increase in the proportion of patients with high Decipher scores with increasing age among GG1 and GG2 (&lt; 55-10.2%, 30.7%, 55-60-15.4%, 25.6%, 60-65-15.9%, 29.7%, 65-70-16.9%, 28.2%, 70-75-17.9%, 30%, and &gt; 75-20.3%, 37.3%, respectively). Furthermore, the prevalence of the PAM50 luminal B subtype (associated with worse prognosis) increased with age among GG1 and GG2 (&lt; 60-22.2%, 40%, 60-65-29.1%, 41.7%, 65-70-28.2%, 39.2%, 70-75-30%, 43.4%, 75-80-33.5%, 44.3%, &gt; 80-34.2%, 52%, respectively). Among higher grade tumors (GG 3-5), no statistically significant differences between the different age groups were observed. MLRA demonstrated that in addition to higher T stage, PSA and GG, each age decile entailed a 20% increased risk for a high Decipher score (OR 1.2, 95% C.I 1.11-1.3, p &lt; 0.001). Conclusions: Older men with lower grade tumors, as opposed to higher grade tumors, harbored worse disease based on genomic risk models. The accepted paradigm of elderly PC patients being treated conservatively based solely on chronologic age, needs to be changed. We provide evidence suggesting the utility of clinical-genomic characterization for better treatment individualization decisions. (GRID; NCT02609269).
Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders
Authors: Vincent Javaugue, Céline Debiais-Delpech, Mathilde Nouvier, Elise Gand, Sophie Chauvet, Laure Ecotiere, Estelle Desport, Jean-Michel Goujon, Vincent Delwail, Stéphanie Guidez, Cécile Tomowiak, Xavier Leleu, Arnaud Jaccard, Nathalie Rioux-Leclerc, Cécile Vigneau, Jean-Paul Fermand, Guy Touchard, Antoine Thierry, Frank Bridoux
Journal: Kidney International (2019)
Letter to the Editor: Acute‐on‐Chronic Liver Failure: Conceptual Divergences
Authors: Ângelo Zambam de Mattos, Angelo Alves de Mattos
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: Mahmud et al.1 evaluated 80,383 outpatients with cirrhosis, finding an incidence of acute‐on‐chronic liver failure (ACLF) of 1.69%, according to the definition of the Asian Pacific Association for the Study of the Liver (APASL), with 28‐day and 90‐day mortality of 41.9% and 56.1%. According to criteria proposed by the Chronic Liver Failure Consortium (CLIF‐C), ACLF incidence was 6.32%, with 28‐day and 90‐day mortality of 37.6% and 50.4%.1 Despite the impressive sample size evaluated, some considerations are necessary. This was a retrospective study, and data regarding respiratory and brain failure were not available exactly as required by CLIF‐C. Therefore, the authors made adaptations to these criteria,1 which may have led to an underestimation of ACLF incidence and might help explain why it was much lower than that found by Piano et al. (25%).2 The authors also highlighted that ACLF incidence and mortality vary according to different criteria.1 We have recently compared not only CLIF‐C and APASL but also North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) definitions for ACLF.3 In our study, the CLIF‐C definition diagnosed ACLF in more patients and had better performance predicting 28‐day mortality (areas under the curve [AUCs] of 0.710, 0.560, and 0.561 for CLIF‐C, APASL, and NACSELD; P = 0.002) and 90‐day mortality (AUCs of 0.760, 0.554, and 0.555 for CLIF‐C, APASL, and NACSELD; P < 0.001).3 Mahmud et al.1 criticized the CLIF‐C criteria for diagnosing ACLF in more patients than APASL criteria and for the fact that ACLF grade 1 had lower mortality. We, however, believe that using a sensitive ACLF definition allows more patients to receive more intensive care. Moreover, we consider that mortality for ACLF grade 1 (19.3% and 32.5% in 28 and 90 days)1 was actually high, comparable with that of sepsis. In a study performed by our group, ACLF grade 1 survival was only 29 days,4 showing the poor prognosis of these patients, who could benefit from more intensive care, including liver transplant. The authors also questioned the validity of the CLIF‐C definition because patients could meet ACLF criteria with “relatively preserved liver function.”1 Cirrhosis is a complex disease, affecting multiple organs, and, therefore, its severity can be reflected by parameters other than bilirubin. In conclusion, we do not agree that the concept of ACLF should necessarily imply “liver‐specific injury”; rather, it should identify patients with cirrhosis who have the worst prognosis.
Early-Life Cadmium Exposure and Bone-Related Biomarkers: A Longitudinal Study in Children
Authors: Annachiara Malin Igra, Marie Vahter, Rubhana Raqib, Maria Kippler
Journal: Environmental Health Perspectives (2019)

Chronic cadmium exposure has been associated with osteotoxicity in adults, but little is known concerning its effects on early growth, which has been shown to be impaired by cadmium.Our objective was to assess the impact of early-life cadmium exposure on bone-related biomarkers and anthropometry at 9 y of age.For 504 children in a mother-child cohort in Bangladesh, cadmium exposure was assessed by concentrations in urine (U-Cd, long-term exposure) and erythrocytes (Ery-Cd, ongoing exposure) at 9 and 4.5 y of age, and in their mothers during pregnancy. Biomarkers of bone remodeling [urinary deoxypyridinoline (DPD), urinary calcium, plasma parathyroid hormone, osteocalcin, vitamin D3, insulin-like growth factor (IGF) 1, IGF binding protein 3, thyroid stimulating hormone] were measured at 9 y of age.In multivariable-adjusted linear models, a doubling of concurrent U-Cd was associated with a mean increase in osteocalcin of [Formula: see text] (95% CI: 0.042, 5.9) and in urinary DPD of [Formula: see text] (95% CI: 12, 32). In a combined exposure model, a doubling of maternal Ery-Cd was associated with a mean increase in urinary DPD of [Formula: see text] (95% CI: [Formula: see text], 30). Stratifying the osteocalcin model by gender ([Formula: see text] 0.001), a doubling of concurrent U-Cd was associated with a mean decrease in osteocalcin of [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) in boys and a mean increase of [Formula: see text] (95% CI: 5.4, 13) in girls. The same pattern was seen with U-Cd at 4.5 y of age ([Formula: see text] 0.016). Children's U-Cd and Ery-Cd, concurrent and at 4.5 y of age, were inversely associated with vitamin D3.Childhood cadmium exposure was associated with several bone-related biomarkers and some of the associations differed by gender. https://doi.org/10.1289/EHP3655.
Identification of response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.
Authors: Jonathan R. Strosberg, Mauro Cives, Marjorie Brelsford, Michael Black, Alan Meeker, Masoumeh Ghayouri
Journal: Journal of Clinical Oncology (2015)

4099 Background: Capecitabine and temozolomide are active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30% to 70%. Several small retrospective series have suggested that MGMT deficiency may predict response to temozolomide, however expression of MGMT has not been validated as a predictive biomarker. Cytotoxic chemotherapy is thought to be most active in aggressive tumors, however the ki-67 index has not been formally evaluated as a predictive factor. It is unclear whether chromosomal instability (which correlates with alternate lengthening of telomeres) predicts response. Methods: 144 patients with pNET who underwent treatment with capecitabine/temozolomide were retrospectively evaluated for radiographic response. The predictive role of ki-67% and MGMT by immunoistochemestry as well as ALT activation by FISH was assessed on up to 59 evaluable archival specimens. Frequently altered genes in pNETs were also sequenced and their status was correlated to the radiographic response. Results: The ORR was 63%. Response to treatment was significantly higher in tumors with ki-67 > 5% (n = 28) as compared to tumors with ki-67 ≤ 5% (n = 31) (ORR: 64% vs 29%; p = 0.006). MGMT status (p = 0.358) and ALT pathway activation (p = 0.174) were not predictive of response. Conclusions: pNETs with ki-67 > 5% are more likely to respond to capecitabine/temozolomide. MGMT status appears to have no correlation with response.
Abstract 14683: Incidence and Predictors of Dangerous Arrhythmias During Pediatric Exercise Tests
Authors: Oliver M Barry, Kimberlee Gauvreau, Jonathan Rhodes, Jeffrey Reichman, Tracy J Curran, Julie Ann O'Neill, Jennifer L Smith, Laura E Bourette, Mark E Alexander
Journal: Circulation (2017)

Introduction: The incidence of dangerous arrhythmias during pediatric exercise stress tests (EST) and criteria for identifying patients at high risk for this adverse event are poorly characterized....
Impact of concurrent medications on outcomes with PD1/PD-L1 inhibitors for metastatic urothelial carcinoma.
Authors: Archana Agarwal, Gregory Russell Pond, Catherine Curran, Amin Nassar, Pier Vitale Nuzzo, Vivek Kumar, Bradley Alexander McGregor, Xiao X. Wei, Lauren Christine Harshman, Toni K. Choueiri, Kerry L. Kilbridge, Guru Sonpavde
Journal: Journal of Clinical Oncology (2019)

435 Background: The impact of concurrent medications (meds) on outcomes with PD1/PD-L1 inhibitors in metastatic urothelial carcinoma (mUC) is unclear. We investigated whether candidate concurrent meds (NSAIDS [N], metformin [M], antibiotics [A], statins [S] and corticosteroids [C]) have an association with outcomes in mUC patients (pts) receiving a PD1/PD-L1 inhibitor. We hypothesized that A and C compromise outcomes, while N, M and S improve outcomes. Methods: Data from mUC pts who received PD1/PD-L1 inhibitors at the Dana-Farber Cancer Institute (DFCI) was obtained. The concurrent medication was required to be administered within 1 month before starting to anytime during PD1/PD-L1 inhibitor therapy. A Cox regression analysis was done to study the association of variables with response and survival. Results: Data was available for 101 pts with mUC who received atezolizumab [n = 52], pembrolizumab [n = 39], nivolumab [n = 9] and durvalumab [n = 1]. Prior platinum had been administered in 74 pts (73.2%), 25 were chemonaive (24.8%) and prior therapy status was unknown in 2 pts (2%). The concurrent meds were N (n = 30), M (n = 7), A (n = 26), S (n = 33) and C (n = 12). The median survival was 57.9 weeks. Response was seen in 26 pts [25.7%]. A was associated with a lower probability of response (11.5%) than those not on A (30.7%), and worse survival (HR = 1.93, 95% CI 1.93 – 3.42, P = 0.024). Pts who received neither A nor C, one of them or both had a response rate (RR) of 30.6%, 20% and 0%, and median survival of 65.3, 53.1 and 14.9 weeks, respectively (HR = 3.02, 95% CI = 1.34-6.83, p = 0.027). Pts who did not receive N, M and S (n = 52) exhibited a median OS of 39.6 weeks, while those who received ≥1 of these meds (n = 49) exhibited a median survival of 160.3 weeks (p = NS). The study is limited by the retrospective design and modest sample size. Conclusions: In this hypothesis-generating study, concurrent antibiotics or corticosteroids compromised outcomes in mUC pts receiving a PD1/PD-L1 inhibitor and receiving both further compromised outcomes. The numerically higher survival with concurrent N, M or S did not attain statistical significance, but requires further study in larger datasets.
Families of network structures – we need both phenomenal and explanatory models
Authors: Tony Ward, Ronald Fischer
Journal: Behavioral and Brain Sciences (2019)

Abstract Symptom network models (SNWMs) play an important role in identifying but not explaining patterns of symptoms. We discuss underlying assumptions of SNWMs and argue that they represent phenomenal models, best suited to detecting patterns among symptoms. SNWMs need to be supplemented with mechanistic models that provide constitutive and etiological explanations of each symptom (network nodes) once relevant patterns have been identified.