tbuckley/cabot-search huggingface dataset:
Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels
Authors: Kausik K. Ray, Robert M. Stoekenbroek, David Kallend, Toshiyuki Nishikido, Lawrence A. Leiter, Ulf Landmesser, R. Scott Wright, Peter L. J. Wijngaard, John J. P. Kastelein
Journal: JAMA Cardiology (2019)

Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.ClinicalTrials.gov identifier: NCT02597127.
Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy
Authors: Nicholas R. Perkons, Ryan M. Kiefer, Michael C. Noji, Mehrdad Pourfathi, Daniel Ackerman, Sarmad Siddiqui, David Tischfield, Enri Profka, Omar Johnson, Stephen Pickup, Anthony Mancuso, Austin Pantel, Michelle R. Denburg, Gregory J. Nadolski, Stephen J. Hunt, Emma E. Furth, Stephen Kadlecek, Terence P. F. Gade
Journal: Hepatology (2019)

Background and Aims Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease—the principal causes of cancer mortality—have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE‐induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. Approach and Results In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE‐induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon‐labeled substrates. Under TAE‐induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP‐MRSI of 1‐ 13 C‐pyruvate and its downstream metabolites, 1‐ 13 C‐lactate and 1‐ 13 C‐alanine, predicted histological viability. Conclusions These studies provide a paradigm for imaging latent, treatment‐refractory cancer cells, suggesting that DNP‐MRSI provides a technology for this application.
Intravitreal Combined Aflibercept + Anti–Platelet-Derived Growth Factor Receptor β for Neovascular Age-Related Macular Degeneration
Authors: Jeffrey S. Heier, Charles C. Wykoff, Nadia K. Waheed, John W. Kitchens, Sunil S. Patel, Robert Vitti, Lorah Perlee, Karen W. Chu, Sergio Leal, Friedrich Asmus, Vladimir Son, Thomas Schmelter, David M. Brown
Journal: Ophthalmology (2019)
Teenage Pregnancy: Doubts, Uncertainties and Psychiatric Disturbance
Authors: Sean Maskey
Journal: Journal of the Royal Society of Medicine (1991)

Fifty-two pregnant teenagers were assessed at 'booking' using the General Health Questionnaire (GHQ 28), a locus of control scale, and five visual analogue 'attitude scales'. Thirty-eight were in the antenatal and 14 in the termination clinic. One quarter had probable psychiatric disorder on the GHQ. The GHQ scores correlated outcome of pregnancy (whether about the planned outcome of pregnancy (whether termination or full term). Locus of control correlated with the Depression scale of the GHQ but not with attitude to pregnancy or choice of termination or delivery. Clinic staff should be alert to the psychiatric risks when seeing teenagers who have marked doubts about their plans when pregnant.
TCT-795 Trends in the Prevalence and In-Hospital Outcomes of Radial Versus Femoral Access in Percutaneous Coronary Intervention: A Report With 158,363 Patients From the Brazilian Nationwide PCI Registry (CENIC)
Authors: Fábio Pinton, Guy Prado, Cristiano Bezerra, Jose Mariani, Carlos Campos, Adriano Caixeta, Marcelo Franken, Pedro A. Lemos
Journal: Journal of the American College of Cardiology (2019)
Integration or Disintegration
Journal: BMJ (1973)

The effect of EU conditionality has been largely
applauded in the
case of enlargement to Central and Eastern Europe
(CEE). Despite
limitations it largely helped the CEE countries
transform from
communist regimes to market economies and liberal
democracies. In
the case of the Western Balkans however, the
application of
conditionality has deviated from this ideal
functioning. This work
examines the case of Serbia where compliance has been
particularly
constrained. It focuses on cooperation with the
International
Criminal Tribunal for the former Yugoslavia and the
case of Kosovo,
and finds shortcomings
in both the EU’s and Serbia’s approach. On the one
hand, the EU has
failed to produce satisfactory initiatives to
encourage substantial
Serbian compliance. On the other hand, compliance is
stalled
because certain aspects of EU conditionality conflict
with the
collective understanding of Serbian national
identity. This two-sided
analysis draws on both rationalist and constructivist
arguments and
gives an in-depth account of Serbian Europeanization.
The work is
therefore useful both to scholars of European Studies
and scholars
of nationalism.
Health System and Beneficiary Costs Associated With Intensive End-of-Life Medical Services
Authors: Risha Gidwani-Marszowski, Steven M. Asch, Vincent Mor, Todd H. Wagner, Katherine Faricy-Anderson, Samantha Illarmo, Gary Hsin, Manali I. Patel, Kavitha Ramchandran, Karl A. Lorenz, Jack Needleman
Journal: JAMA Network Open (2019)

Despite recommendations to reduce intensive medical treatment at the end of life, many patients with cancer continue to receive such services. To quantify expected beneficiary and health system costs incurred in association with receipt of intensive medical services in the last month of life. This retrospective cohort study used data collected nationally from Medicare and the Veterans Health Administration for care provided in fiscal years 2010 to 2014. Participants were 48 937 adults aged 66 years or older who died of solid tumor and were continuously enrolled in fee-for-service Medicare and the Veterans Health Administration in the 12 months prior to death. The data were analyzed from February to August 2019. American Society of Clinical Oncology metrics regarding medically intensive services provided in the last month of life, including hospital stay, intensive care unit stay, chemotherapy, 2 or more emergency department visits, or hospice for 3 or fewer days. Costs in the last month of life associated with receipt of intensive medical services were evaluated for both beneficiaries and the health system. Costs were estimated from generalized linear models, adjusting for patient demographics and comorbidities and conditioning on geographic region. Of 48 937 veterans who received care through the Veterans Health Administration and Medicare, most were white (90.8%) and male (98.9%). More than half (58.9%) received at least 1 medically intensive service in the last month of life. Patients who received no medically intensive service generated a mean (SD) health system cost of $7660 ($1793), whereas patients who received 1 or more medically intensive services generated a mean (SD) health system cost of $23 612 ($5528); thus, the additional financial consequence to the health care system for medically intensive services was $15 952 (95% CI, $15 676-$16 206; P < .001). The biggest contributor to these differences was $21 093 (95% CI, $20 364-$21 689) for intensive care unit stay, while the smallest contributor was $3460 (95% CI, $2927-$3880) for chemotherapy. Mean (SD) expected beneficiary costs for the last month of life were $133 ($50) for patients with no medically intensive service and $1257 ($408) for patients with at least 1 medically intensive service (P < .001). Given the low income of many elderly patients in the United States, the financial consequences of medically intensive services may be substantial. Costs of medically intensive services at the end of life, including patient financial consequences, should be considered by both physicians and families.
A Telephone-Based Dementia Care Management Intervention—Finding the Time to Listen
Authors: Jennifer Tjia
Journal: JAMA Internal Medicine (2019)

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 Internal Medicine 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 Internal Medicine journal
T-Cell Receptor Stimulation Enhances the Expansion and Function of CD19 Chimeric Antigen Receptor–Expressing T Cells
Authors: Natalia Lapteva, Margaret Gilbert, Iulia Diaconu, Lisa A. Rollins, Mina Al-Sabbagh, Swati Naik, Robert A. Krance, Tamara Tripic, Manasa Hiregange, Darshana Raghavan, Olga Dakhova, Rayne H. Rouce, Hao Liu, Bilal Omer, Barbara Savoldo, Gianpietro Dotti, Conrad Russel Cruz, Keli Sharpe, Melissa Gates, Aaron Orozco, April Durett, Elizabeth Pacheco, Adrian P. Gee, Carlos A. Ramos, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney
Journal: Clinical Cancer Research (2019)

Current protocols for CD19 chimeric antigen receptor-expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells.We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant.Absent virus reactivation, we saw no CD19.CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19+ B cells. Five patients remain in remission at 42-60+ months.Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.
TCT-56 Impact of Neoatherosclerosis on Clinical Outcomes After Repeat Revascularization of In-Stent Restenosis of Second-Generation Drug-Eluting Stents
Authors: Zhaoyang Chen, Mitsuaki Matsumura, Gary Mintz, Masahiko Noguchi, Tatsuhiro Fujimura, Eisuke Usui, Ziad Ali, Jeffrey W. Moses, Allen Jeremias, Richard Shlofmitz, Akiko Maehara
Journal: Journal of the American College of Cardiology (2019)
TCT-83 Effects of Catheter-Based Renal Denervation on Left Ventricular Function Assessed by 2-Dimensional Speckle Tracking Echocardiography
Authors: Lucas Lauder, Felix Mahfoud, Naemi Schreiber, Sean Scholz, Valerie Pavlicek, Christian Ukena, Michael Böhm, Sebastian Ewen
Journal: Journal of the American College of Cardiology (2019)
Erratum: Clinical impact of bone marrow morphology for the diagnosis of essential thrombocythemia: comparison between the BCSH and the WHO criteria
Authors: H Gisslinger, G Jeryczynski, B Gisslinger, A Wölfler, S Burgstaller, V Buxhofer-Ausch, M Schalling, M-T Krauth, A-I Schiefer, C Kornauth, I Simonitsch-Klupp, C Beham-Schmid, L Müllauer, J Thiele
Journal: Leukemia (2017)
TCT-739 Impact of Waiting Time From Referral to Procedural Date in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Janarthanan Sathananthan, Sandra Lauck, Lilian Ding, Maggie Yu, Mark Hensey, Bonnie Catlin, Albert Chan, Jay Charania, Anson Cheung, Richard Cook, Jian Ye, Jopie Polderman, Simon Robinson, Sean Virani, Daniel Wong, Harindra Wijeysundera, David Wood, John Webb
Journal: Journal of the American College of Cardiology (2019)
Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial
Authors: Marcia S. Brose, Martin Schlumbeger, Michael Jeffers, Christian Kappeler, Gerold Meinhardt, Carol E.A. Peña
Journal: Clinical Cancer Research (2019)

The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION.Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes.Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38-2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37-3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52-2.71; P < 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57-2.87; P < 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P < 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40-0.94), P = 0.022; placebo = 0.49 (0.29-0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit.We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.
TCT-257 Effect of Post-Dilatation Irrespective of the Degree of Residual Paravalvular Leakage Following Balloon-Expandable Transcatheter Aortic Valve Replacement
Authors: Tomohiro Kawaguchi, Kyohei Yamaji, Akihiro Isotani, Shinya Ito, Shirai Shinichi, Kenji Ando
Journal: Journal of the American College of Cardiology (2019)
Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice
Authors: Theun de Groot, Lena K. Ebert, Birgitte Mønster Christensen, Karolina Andralojc, Lydie Cheval, Alain Doucet, Cungui Mao, Ruben Baumgarten, Benjamin E. Low, Roger Sandhoff, Michael V. Wiles, Peter M.T. Deen, Ron Korstanje
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Lithium causes nephrogenic diabetes insipidus and hypercalcemia in 20% and 10% of patients, respectively, and may lead to metabolic acidosis. To determine the potential role of genetic predisposition in these adverse effects, the authors fed mice from 29 genetically different inbred strains a normal or a lithium-supplemented diet. Some strains developed adverse effects, whereas others did not. Genome-wide association studies revealed eight loci containing different candidate genes that were associated with development of lithium-induced nephrogenic diabetes insipidus. Of these, Acer2 is specifically expressed in the collecting duct; mice lacking Acer2 were more likely to develop lithium-induced nephrogenic diabetes insipidus. These findings demonstrate the importance of genetic variation in susceptibility for lithium-induced adverse effects in mice, and the genes identified may facilitate subsequent identification of human susceptibility genes. Background Lithium, mainstay treatment for bipolar disorder, causes nephrogenic diabetes insipidus and hypercalcemia in about 20% and 10% of patients, respectively, and may lead to acidosis. These adverse effects develop in only a subset of patients treated with lithium, suggesting genetic factors play a role. Methods To identify susceptibility genes for lithium-induced adverse effects, we performed a genome-wide association study in mice, which develop such effects faster than humans. On day 8 and 10 after assigning female mice from 29 different inbred strains to normal chow or lithium diet (40 mmol/kg), we housed the animals for 48 hours in metabolic cages for urine collection. We also collected blood samples. Results In 17 strains, lithium treatment significantly elevated urine production, whereas the other 12 strains were not affected. Increased urine production strongly correlated with lower urine osmolality and elevated water intake. Lithium caused acidosis only in one mouse strain, whereas hypercalcemia was found in four strains. Lithium effects on blood pH or ionized calcium did not correlate with effects on urine production. Using genome-wide association analyses, we identified eight gene-containing loci, including a locus containing Acer2 , which encodes a ceramidase and is specifically expressed in the collecting duct. Knockout of Acer2 led to increased susceptibility for lithium-induced diabetes insipidus development. Conclusions We demonstrate that genome-wide association studies in mice can be used successfully to identify susceptibility genes for development of lithium-induced adverse effects. We identified Acer2 as a first susceptibility gene for lithium-induced diabetes insipidus in mice.
Human Organoids: Tools for Understanding Biology and Treating Diseases
Authors: Frans Schutgens, Hans Clevers
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

Organoids are in vitro-cultured three-dimensional structures that recapitulate key aspects of in vivo organs. They can be established from pluripotent stem cells and from adult stem cells, the latter being the subject of this review. Organoids derived from adult stem cells exploit the tissue regeneration process that is driven by these cells, and they can be established directly from the healthy or diseased epithelium of many organs. Organoids are amenable to any experimental approach that has been developed for cell lines. Applications in experimental biology involve the modeling of tissue physiology and disease, including malignant, hereditary, and infectious diseases. Biobanks of patient-derived tumor organoids are used in drug development research, and they hold promise for developing personalized and regenerative medicine. In this review, we discuss the applications of adult stem cell-derived organoids in the laboratory and the clinic.
Ticagrelor with or without Aspirin in High-Risk Patients after PCI
Authors: Roxana Mehran, Usman Baber, Samin K. Sharma, David J. Cohen, Dominick J. Angiolillo, Carlo Briguori, Jin Y. Cha, Timothy Collier, George Dangas, Dariusz Dudek, Vladimír Džavík, Javier Escaned, Robert Gil, Paul Gurbel, Christian W. Hamm, Timothy Henry, Kurt Huber, Adnan Kastrati, Upendra Kaul, Ran Kornowski, Mitchell Krucoff, Vijay Kunadian, Steven O. Marx, Shamir R. Mehta, David Moliterno, E. Magnus Ohman, Keith Oldroyd, Gennaro Sardella, Samantha Sartori, Richard Shlofmitz, P. Gabriel Steg, Giora Weisz, Bernhard Witzenbichler, Ya-ling Han, Stuart Pocock, C. Michael Gibson
Journal: New England Journal of Medicine (2019)

Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI).