tbuckley/cabot-search huggingface dataset:
AB0574 BENEFITS OF ILOPROST IN LONG – TERM STABILIZATION OR IMPROVEMENT IN NEOANGIOGENESIS IN SYSTEMIC SCLEROSIS: A 15 YEARS OBSERVATION COHORT
Authors: P. Faggioli, L. Castelnovo, A. Tamburello, A. Laria, A. M. Lurati, A. Mazzone
Journal: Annals of the Rheumatic Diseases (2020)

Background: In Systemic Sclerosis (SSc) fibrosis is due to microcirculation damage with capillary necrosis, arteriolar intimal proliferation and local ischemia. loprost (ILO) is used IV for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in (SSc). We have already described (1) an improvement of peripheral vascularization with ILO, observed after 3 years treatment by capillaroscopy with an increase in the capillary number and mild regression of avascular areas and pericapillar oedema Objectives: Our aim was to observe capillaroscopic changes in a cohort of 26 patients treated with ILO, once a month (25 – 50 ng each infusion) for an average time of 15 years Methods: We evaluated the initial and 2019 capillaroscopic picture of 26 SSc patients (24 W,2 M; median age 63.8Y) in continuous treatment with monthly infusion of ILO from 2004 to today. 6/26 were SCL70 positive;the remainder was positive for anticentromere Ab Results: We documented stability of capillaroscopic picture in 62% of patients,an improvement in 19% and a worsening (mainly from early to active pattern) in 19%. Low adherence to therapy was observed among the worsened patients. Out of 8 patients with onset ulcers, only 3 patients still have skin ulcers, all with late stable capillaroscopic picture from onset.We have not documented serious adverse events Conclusion: Our observations confirm the efficacy and safety of ILO in the treatment of SSc even after many years of treatment, resulting in a stabilization of microvascular damage, independent of disease severity. References: [1]Possible role of iloprost (stable analog of PG12) in promoting neoangiogenesis in systemic sclerosis. Faggioli P, Giani L, Mazzone A. Clin Exp Rheumatol. 2006 Mar-Apr;24(2):220-1. No abstract available Disclosure of Interests: None declared
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
Authors: Rafik Tadros, Catherine Francis, Xiao Xu, Alexa M. C. Vermeer, Andrew R. Harper, Roy Huurman, Ken Kelu Bisabu, Roddy Walsh, Edgar T. Hoorntje, Wouter P. te Rijdt, Rachel J. Buchan, Hannah G. van Velzen, Marjon A. van Slegtenhorst, Jentien M. Vermeulen, Joost Allard Offerhaus, Wenjia Bai, Antonio de Marvao, Najim Lahrouchi, Leander Beekman, Jacco C. Karper, Jan H. Veldink, Elham Kayvanpour, Antonis Pantazis, A. John Baksi, Nicola Whiffin, Francesco Mazzarotto, Geraldine Sloane, Hideaki Suzuki, Deborah Schneider-Luftman, Paul Elliott, Pascale Richard, Flavie Ader, Eric Villard, Peter Lichtner, Thomas Meitinger, Michael W. T. Tanck, J. Peter van Tintelen, Andrew Thain, David McCarty, Robert A. Hegele, Jason D. Roberts, Julie Amyot, Marie-Pierre Dubé, Julia Cadrin-Tourigny, Geneviève Giraldeau, Philippe L. L’Allier, Patrick Garceau, Jean-Claude Tardif, S. Matthijs Boekholdt, R. Thomas Lumbers, Folkert W. Asselbergs, Paul J. R. Barton, Stuart A. Cook, Sanjay K. Prasad, Declan P. O’Regan, Jolanda van der Velden, Karin J. H. Verweij, Mario Talajic, Guillaume Lettre, Yigal M. Pinto, Benjamin Meder, Philippe Charron, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Arthur A. M. Wilde, Hugh Watkins, Paul M. Matthews, James S. Ware, Connie R. Bezzina
Journal: Nature Genetics (2021)
Prognosis in Childhood Epilepsy
Authors: Jean Holowach Thurston, Don L. Thurston, Barbara B. Hixon, Amy J. Keller
Journal: New England Journal of Medicine (1982)

To evaluate the risk of relapse in children with epilepsy whose anticonvulsant therapy has been withdrawn after prolonged control, we studied 148 such children for 15 to 23 years or until relapse. Forty-one of the 148 patients (28 per cent) had recurrence of seizures; of these, 35 (85 per cent) had relapses within five years of drug withdrawal. Factors associated with an increased risk of relapse were a long duration of epilepsy before control, neurologic dysfunction, and jacksonian seizures or combinations of seizure types. We found no association between risk of recurrence and age at onset of epilepsy, total number of seizures before control, age at discontinuation of therapy, electroencephalographic abnormalities, or family history of epilepsy. We conclude that children who do not have the additional risk factors noted above have an excellent chance of remaining seizure free after the withdrawal of anticonvulsant drugs.
Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): Long-term results from CheckMate 040.
Authors: Anthony B. El-Khoueiry, Thomas Yau, Yoon-Koo Kang, Tae-You Kim, Armando Santoro, Bruno Sangro, Ignacio Melero, Masatoshi Kudo, Ming-Mo Hou, Ana Matilla, Francesco Tovoli, Jennifer J. Knox, Aiwu Ruth He, Bassel F. El-Rayes, Mirelis Acosta-Rivera, Ho Yeong Lim, Arteid Memaj, Ashwin Reddy Sama, Chiun Hsu
Journal: Journal of Clinical Oncology (2021)

269 Background: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) followed by NIVO 240 mg Q2W is approved in the US for sorafenib-treated pts with aHCC based on initial results from CheckMate 040 (NCT01658878), which reported objective response rate (ORR) of 32% and median overall survival (mOS) of 22.8 months (mo). 1 We present 44-mo long-term follow-up results from the CheckMate 040 NIVO+IPI cohort. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Safety and tolerability, ORR (blinded independent central review per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS were assessed. Data cutoff was May 26, 2020. Results: 148 pts were randomized. Minimum follow-up was 44 mo. mOS remained at 22.2 mo in arm A, 12.5 mo in arm B, and 12.7 mo in arm C; 36-mo OS rates were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with DOR approaching 4 years in some cases. DCR was higher in arm A than arms B and C. In all arms, responses were observed regardless of baseline programmed death ligand 1 expression ( &lt; 1% or ≥ 1%) or baseline alpha-fetoprotein level ( &lt; 400 µg/L or ≥ 400 µg/L). Pts with hepatitis B or C virus (HBV or HCV) etiology had higher ORR than uninfected pts in arms B (29% vs 43% vs 9%) and C (31% vs 42% vs 0%). ORR was independent of etiology in arm A (HBV, 32%; HCV, 29%; uninfected, 31%). Additional efficacy data are in the table. There were no additional discontinuations due to treatment-related adverse events or immune-mediated adverse events (IMAEs) since the primary analysis. IMAEs were reported more frequently in arm A than arms B and C; the most common were rash, hepatitis, and adrenal insufficiency. Most IMAEs were reversible and resolved when treated using established algorithms. Conclusions: At a minimum follow-up of 44 mo, second-line NIVO1+IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in aHCC. The safety profile was manageable and no new safety signals were identified with longer follow-up. Clinical trial information: NCT01658878. [Table: see text]
Performances of Targeted RNA Sequencing for the Analysis of Fusion Transcripts, Gene Mutation, and Expression in Hematological Malignancies
Authors: Sandrine Hayette, Béatrice Grange, Maxime Vallee, Claire Bardel, Sarah Huet, Isabelle Mosnier, Kaddour Chabane, Thomas Simonet, Marie Balsat, Maël Heiblig, Isabelle Tigaud, Franck E Nicolini, Sylvain Mareschal, Gilles Salles, Pierre Sujobert
Journal: HemaSphere (2021)

RNA sequencing holds great promise to improve the diagnostic of hematological malignancies, because this technique enables to detect fusion transcripts, to look for somatic mutations in oncogenes, and to capture transcriptomic signatures of nosological entities. However, the analytical performances of targeted RNA sequencing have not been extensively described in diagnostic samples. Using a targeted panel of 1385 cancer-related genes in a series of 100 diagnosis samples and 8 controls, we detected all the already known fusion transcripts and also discovered unknown and/or unsuspected fusion transcripts in 12 samples. Regarding the analysis of transcriptomic profiles, we show that targeted RNA sequencing is performant to discriminate acute lymphoblastic leukemia entities driven by different oncogenic translocations. Additionally, we show that 86% of the mutations identified at the DNA level are also detectable at the messenger RNA (mRNA) level, except for nonsense mutations that are subjected to mRNA decay. We conclude that targeted RNA sequencing might improve the diagnosis of hematological malignancies. Standardization of the preanalytical steps and further refinements of the panel design and of the bioinformatical pipelines will be an important step towards its use in standard diagnostic procedures.
The clinical spectrum of COVID-19–associated cutaneous manifestations: An Italian multicenter study of 200 adult patients
Authors: Angelo Valerio Marzano, Giovanni Genovese, Chiara Moltrasio, Valeria Gaspari, Pamela Vezzoli, Vincenzo Maione, Cosimo Misciali, Paolo Sena, Annalisa Patrizi, Annamaria Offidani, Pietro Quaglino, Renato Arco, Marzia Caproni, Miriam Rovesti, Giorgio Bordin, Sebastiano Recalcati, Concetta Potenza, Claudio Guarneri, Gabriella Fabbrocini, Carlo Tomasini, Mariarita Sorci, Maurizio Lombardo, Paolo Gisondi, Andrea Conti, Giovanni Casazza, Ketty Peris, Piergiacomo Calzavara-Pinton, Emilio Berti
Journal: Journal of the American Academy of Dermatology (2021)
Ventral arkypallidal neurons inhibit accumbal firing to promote reward consumption
Authors: Yvan M. Vachez, Jessica R. Tooley, Kavitha Abiraman, Bridget Matikainen-Ankney, Eric Casey, Tom Earnest, Leana M. Ramos, Hanna Silberberg, Elizabeth Godynyuk, Olivia Uddin, Lauren Marconi, Claire E. Le Pichon, Meaghan C. Creed
Journal: Nature Neuroscience (2021)
Using Autoencoders for Imputing Missing Data in eGFR Decline Trajectories of Patients with CKD
Authors: Davina J. Zamanzadeh, Panayiotis Petousis, Tyler A. Davis, Anders O. Garlid, Xiaoyan Wang, Keith C. Norris, Obidiugwu Duru, Katherine R. Tuttle, Alex Bui, Susanne B. Nicholas
Journal: Journal of the American Society of Nephrology (2020)
Risk of Blindness Among Patients With Diabetes and Newly Diagnosed Diabetic Retinopathy
Authors: Charles C. Wykoff, Rahul N. Khurana, Quan Dong Nguyen, Scott P. Kelly, Flora Lum, Rebecca Hall, Ibrahim M. Abbass, Anna M. Abolian, Ivaylo Stoilov, Tu My To, Vincent Garmo
Journal: Diabetes Care (2021)

OBJECTIVE To evaluate the association between initial diabetic retinopathy (DR) severity/risk of blindness in patients with newly diagnosed DR/good vision in the U.S. RESEARCH DESIGN AND METHODS This retrospective cohort study evaluated adult patients with good vision (20/40 or better) and newly diagnosed DR between 1 January 2013 and 31 December 2017 (index date) in the American Academy of Ophthalmology’s Intelligent Research in Sight (IRIS) Registry. The primary exposure of interest was DR severity at index: mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). The main outcome measure was development of sustained blindness (SB), defined as study eyes with Snellen visual acuity readings of 20/200 or worse at two separate visits ≥3 months apart that did not improve beyond 20/100. RESULTS Among 53,535 eligible eyes (mean follow-up 662.5 days), 678 (1.3%) eyes developed SB. Eyes with PDR at index represented 10.5% (5,629 of 53,535) of the analysis population but made up 26.5% (180 of 678) of eyes that developed SB. Kaplan-Meier analysis revealed that eyes with moderate NPDR, severe NPDR, and PDR at index were 2.6, 3.6, and 4.0 times more likely, respectively, to develop SB after 2 years of DR diagnosis versus eyes with mild DR at index. In a Cox proportional hazards model adjusted for index characteristics/development of ocular conditions during follow-up, eyes with PDR had an increased risk of developing SB versus eyes with mild NPDR at index (hazard ratio 2.26 [95% CI 2.09−2.45]). CONCLUSIONS In this longitudinal ophthalmologic registry population involving eyes with good vision, more advanced DR at first diagnosis was a significant risk factor for developing SB.
Mode and dynamics of vanA-type vancomycin resistance dissemination in Dutch hospitals
Authors: Sergio Arredondo-Alonso, Janetta Top, Jukka Corander, Rob J. L. Willems, Anita C. Schürch
Journal: Genome Medicine (2021)

Enterococcus faecium is a commensal of the gastrointestinal tract of animals and humans but also a causative agent of hospital-acquired infections. Resistance against glycopeptides and to vancomycin has motivated the inclusion of E. faecium in the WHO global priority list. Vancomycin resistance can be conferred by the vanA gene cluster on the transposon Tn1546, which is frequently present in plasmids. The vanA gene cluster can be disseminated clonally but also horizontally either by plasmid dissemination or by Tn1546 transposition between different genomic locations.We performed a retrospective study of the genomic epidemiology of 309 vancomycin-resistant E. faecium (VRE) isolates across 32 Dutch hospitals (2012-2015). Genomic information regarding clonality and Tn1546 characterization was extracted using hierBAPS sequence clusters (SC) and TETyper, respectively. Plasmids were predicted using gplas in combination with a network approach based on shared k-mer content. Next, we conducted a pairwise comparison between isolates sharing a potential epidemiological link to elucidate whether clonal, plasmid, or Tn1546 spread accounted for vanA-type resistance dissemination.On average, we estimated that 59% of VRE cases with a potential epidemiological link were unrelated which was defined as VRE pairs with a distinct Tn1546 variant. Clonal dissemination accounted for 32% cases in which the same SC and Tn1546 variants were identified. Horizontal plasmid dissemination accounted for 7% of VRE cases, in which we observed VRE pairs belonging to a distinct SC but carrying an identical plasmid and Tn1546 variant. In 2% of cases, we observed the same Tn1546 variant in distinct SC and plasmid types which could be explained by mixed and consecutive events of clonal and plasmid dissemination.In related VRE cases, the dissemination of the vanA gene cluster in Dutch hospitals between 2012 and 2015 was dominated by clonal spread. However, we also identified outbreak settings with high frequencies of plasmid dissemination in which the spread of resistance was mainly driven by horizontal gene transfer (HGT). This study demonstrates the feasibility of distinguishing between modes of dissemination with short-read data and provides a novel assessment to estimate the relative contribution of nested genomic elements in the dissemination of vanA-type resistance.
Association of Cannabis Use With Self-harm and Mortality Risk Among Youths With Mood Disorders
Authors: Cynthia A. Fontanella, Danielle L. Steelesmith, Guy Brock, Jeffrey A. Bridge, John V. Campo, Mary A. Fristad
Journal: JAMA Pediatrics (2021)

Cannabis use and cannabis use disorder (CUD) are common among youths and young adults with mood disorders, but the association of CUD with self-harm, suicide, and overall mortality risk is poorly understood in this already vulnerable population.To examine associations of CUD with self-harm, suicide, and overall mortality risk in youths with mood disorders.A population-based retrospective cohort study was performed using Ohio Medicaid claims data linked with death certificate data. The analysis included 204 780 youths (aged 10-24 years) with a diagnosis of mood disorders between July 1, 2010, and December 31, 2017, who were followed up to 365 days from the index diagnostic claim until the end of enrollment, the self-harm event, or death. Statistical analysis was performed from April 4 to July 17, 2020.Physician-diagnosed CUD defined using outpatient and inpatient claims from 180 days prior to the index mood disorder diagnostic claim through the 365-day follow-up period.Nonfatal self-harm, all-cause mortality, and deaths by suicide, unintentional overdose, motor vehicle crashes, and homicide. Marginal structural models using inverse probability weights examined associations between CUD and outcomes.This study included 204 780 youths (133 081 female participants [65.0%]; mean [SD] age at the time of mood disorder diagnosis, 17.2 [4.10] years). Cannabis use disorder was documented for 10.3% of youths with mood disorders (n = 21 040) and was significantly associated with older age (14-18 years vs 10-13 years: adjusted risk ratio [ARR], 9.35; 95% CI, 8.57-10.19; and 19-24 years vs 10-13 years: ARR, 11.22; 95% CI, 10.27-12.26), male sex (ARR, 1.79; 95% CI, 1.74-1.84), Black race (ARR, 1.39; 95% CI, 1.35-1.44), bipolar or other mood disorders (bipolar disorders: ARR, 1.24; 95% CI, 1.21-1.29; other mood disorders: ARR, 1.20; 95% CI, 1.15-1.25), prior history of self-harm (ARR, 1.66; 95% CI, 1.52-1.82), previous mental health outpatient visits (ARR, 1.26; 95% CI, 1.22-1.30), psychiatric hospitalizations (ARR, 1.66; 95% CI, 1.57-1.76), and mental health emergency department visits (ARR, 1.54; 95% CI, 1.47-1.61). Cannabis use disorder was significantly associated with nonfatal self-harm (adjusted hazard ratio [AHR], 3.28; 95% CI, 2.55-4.22) and all-cause mortality (AHR, 1.59; 95% CI, 1.13-2.24), including death by unintentional overdose (AHR, 2.40; 95% CI, 1.39-4.16) and homicide (AHR, 3.23; 95% CI, 1.22-8.59). Although CUD was associated with suicide in the unadjusted model, it was not significantly associated in adjusted models.Cannabis use disorder is a common comorbidity and risk marker for self-harm, all-cause mortality, and death by unintentional overdose and homicide among youths with mood disorders. These findings should be considered as states contemplate legalizing medical and recreational marijuana, both of which are associated with increased CUD.
Real-world genomic and treatment landscape in advanced colorectal cancer identifies treatment differences pre- and post-ctDNA genomic profiling.
Authors: Junhua Yu, Kanwal Pratap Singh Raghav, Aparna Raj Parikh, David Hanna, Enrique Marino, Victoria M. Raymond, Rebecca Nagy, Nicole Zhang, Ryan Bruce Corcoran, Scott Kopetz, John H. Strickler, Kathryn Lang
Journal: Journal of Clinical Oncology (2021)

39 Background: Clinical insights gained from real-world data have led to numerous advances in oncology including new and expanded drug approvals and an understanding of real-world clinical utilization. In this precision oncology age, integrating real-world clinical data with genomic data can lead to further advancements. We aimed to understand the genomic and treatment landscape in advanced colorectal cancer (aCRC) by leveraging a uniquely large and detailed clinical-genomic database. Methods: The GuardantINFORM (Guardant Health) database comprises aggregated commercial payer health claims and de-identified records from over 100,000 individuals with comprehensive ctDNA results (Guardant360). GuardantINFORM was queried for patients (pts) with a diagnosis of CRC. Pts with fewer than two pharmacy claims prior to or after the first ctDNA test were excluded from the regimen analysis. Latest claims data was truncated as of 8/31/2020. Results: 10,845 pts had a total of 13,510 ctDNA tests (1 – 19 tests/pt). The first ctDNA test date was from 06/2014 - 06/2020. The majority of pts had one ctDNA test (86.7%) while 5% had three or more tests. 87.9% of ctDNA tests had at least one genomic alteration identified, with the distribution of alterations consistent with prior reports (Table). 78% of pts had at least two pharmacy claims before and/or after the first ctDNA test. Of those pts with at least one CRC treatment, the most commonly prescribed CRC regimens up to one year prior to the first ctDNA test were FOLFOX +/- bevacizumab (16%, 18%), FOLFIRI +/- bevacizumab (17%, 11%), capecitabine (15%), 5-FU (12%), and regorafenib (5.2%). Anti-EGFR mono and combination therapy was reported in 6% and 16% of pts pre ctDNA testing. Immune checkpoint inhibitor (ICPi) mono and combination therapy was reported in 2% and 0.5% of pts. The most commonly prescribed CRC regimens post first ctDNA test were capecitabine (16%), FOLIRI +/- bevacizumab (15%, 13%), tipiracil and trifluridine (15%), FOLFOX +/- bevacizumab (12%, 14%), 5-FU (11%), and regorafenib (10%). Anti-EGFR mono and combination therapy was reported in 8% and 18% of pts post ctDNA testing. ICPi mono and combination therapy was reported in 5% and 1% of pts. Conclusions: Using a large and uniquely detailed clinical-genomic dataset, we produced results that replicate the observed distribution of ctDNA identified mutations present in aCRC. This genomic information combined with real-world clinical data provides valuable insights into the variety of longitudinal treatments, including before and after comprehensive ctDNA genomic profiling, allowing for detailed outcomes research, especially focused on precision oncology. [Table: see text]
Apps and the Woman With Gestational Diabetes Mellitus
Authors: Jincy Immanuel, David Simmons
Journal: Diabetes Care (2021)

Gestational diabetes mellitus (GDM) affects 1–45% of pregnancies depending on the population and diagnostic criteria selected (1). A meta-analysis with 12 randomized controlled trials (RCTs) showed that GDM management improves pregnancy outcomes (2). GDM management involves counseling, dietary modification, physical activity, glucose monitoring, and, where glycemic thresholds are exceeded, supplemental pharmacological therapies. Implementation varies, with possible consequences for the pregnancy outcomes. For example, the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and Maternal–Fetal Medicine Units Network (MFMUN) RCTs, the two largest GDM treatment trials, differed in their insulin use (20% vs. 8%, respectively) and outcomes (3,4). Within the MFNUM RCT, the median glucose achieved was 10–12 mg/dL (0.6 mmol/L) higher in the insulin-treated than the non–insulin-treated group, particularly after dinner, when 50% of the self–blood glucose monitoring results were over the target glucose (median glucose was 120 mg/dL [6.7 mmol/L]). The more self–blood glucose monitoring results occur above target, the greater the chance of an adverse pregnancy outcome. In one study, adverse outcomes occurred in 25% vs. 60% of births among those with none vs. >30% above-target results, respectively (5). There are multiple barriers to GDM management for women with GDM (6). Besides a range of socioeconomic, service, and access barriers, women may experience misunderstanding or confusion over the advice provided, as well as a range of emotional and psychological challenges. Meanwhile, the increasing number of women with GDM (7) has created greater pressure on health care providers to streamline their services with different models of care, often sharing management with non–diabetes service staff (8).

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