tbuckley/cabot-search huggingface dataset:
Thrombolysis before Thrombectomy — To Be or DIRECT-MT?
Authors: Gregory W. Albers
Journal: New England Journal of Medicine (2020)

Endovascular thrombectomy has been shown to be safe and effective for the treatment of appropriately selected patients with acute ischemic stroke up to 24 hours after symptom onset.1-3 Several trials are attempting to expand the selection criteria for thrombectomy, in the hope of finding additional populations of patients who will benefit and in an effort to improve delivery of this therapy. An important question is whether the initiation of therapy with alteplase, an intravenous thrombolytic agent that is effective for treating ischemic stroke, provides additional benefit over thrombectomy performed without preceding intravenous thrombolytic treatment. A potential advantage of a strategy . . .
Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin
Authors: R K Ross, A Paganini-Hill, P C Wan, M C Pike
Journal: JNCI Journal of the National Cancer Institute (2000)

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4½ years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR5 = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR5 = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR5= 1.06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR5 = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR5= 1.09; 95% CI = 0.88-1.35), but this difference was not statistically significant. Conclusions: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.
Model-Based Detection of Whole-Genome Duplications in a Phylogeny
Authors: Arthur Zwaenepoel, Yves Van de Peer
Journal: Molecular Biology and Evolution (2020)

Ancient whole-genome duplications (WGDs) leave signatures in comparative genomic data sets that can be harnessed to detect these events of presumed evolutionary importance. Current statistical approaches for the detection of ancient WGDs in a phylogenetic context have two main drawbacks. The first is that unwarranted restrictive assumptions on the "background" gene duplication and loss rates make inferences unreliable in the face of model violations. The second is that most methods can only be used to examine a limited set of a priori selected WGD hypotheses and cannot be used to discover WGDs in a phylogeny. In this study, we develop an approach for WGD inference using gene count data that seeks to overcome both issues. We employ a phylogenetic birth-death model that includes WGD in a flexible hierarchical Bayesian approach and use reversible-jump Markov chain Monte Carlo to perform Bayesian inference of branch-specific duplication, loss, and WGD retention rates across the space of WGD configurations. We evaluate the proposed method using simulations, apply it to data sets from flowering plants, and discuss the statistical intricacies of model-based WGD inference.
Feelings of obligation are valuations of signaling-mediated social payoffs
Authors: Amanda Rotella, Adam Maxwell Sparks, Pat Barclay
Journal: Behavioral and Brain Sciences (2020)

Abstract We extend Tomasello's framework by addressing the functional challenge of obligation. If the long-run social consequences of a decision are sufficiently costly, obligation motivates the actor to forgo potential immediate benefits in favor of long-term social interests. Thus, obligation psychology balances the downstream socially-mediated payoffs from a decision. This perspective can predict when and why obligation will be experienced.
Assessment of microbial landscape and colon cytoprotection indices in patients with chronic constipations
Authors: Yu.M. Stepanov, O.M. Vlasova, I.A. Klenina
Journal: GASTROENTEROLOGY (2020)

Актуальность. В статье рассматриваются вопросы хронических запоров. Показаны результаты собственных исследований, в которых определялось содержание короткоцепочечных жирных кислот (КЖК) в кале и состояние микробиоценоза у пациентов до и на фоне лечения препаратом Изиду. Материалы и методы. Под наблюдением находилось 10 больных в возрасте от 18 до 65 лет с хроническим запором, от которого они страдали около 10 лет. Пациенты принимали комплексное слабительное средство Изиду по 3 капсулы в сутки. С целью оценки содержания КЖК и микробного пейзажа больным (6 женщин, 4 мужчины) дважды — до приема препарата Изиду и через 2 недели после его приема — проведено исследование кала. Определение КЖК осуществляли методом хроматографического исследования с использованием аппаратно-программного комплекса для медицинских исследований на базе газового хроматографа «Хроматэк-Кристалл 5000». Результаты. Выявлено существенное повышение содержания в кале КЖК и снижение содержания лактобактерий до начала лечения. После лечения содержание уксусной кислоты достоверно снизилось в 3,9 раза до среднего значения (0,011 ± 0,005) мкл/мл (р &lt; 0,05). Содержание масляной кислоты у 90 % пациентов было существенно повышено по сравнению с контролем и отмечалось на уровне 0,018–0,131 мкл/мл, среднее значение составляло (0,0499 ± 0,004) мкл/мл, что было достоверно выше контрольных показателей (р &lt; 0,001). После лечения наблюдалось увеличение содержания масляной кислоты до (0,061 ± 0,003) мкл/мл (р &lt; 0,05). После применения препарата Изиду у 60 % пациентов состав микрофлоры кишечника улучшался, существенно повысилось содержание микроорганизмов рода Lactobacillus (105 КОЕ/г фекалий), показатели содержания других микроорганизмов были в диапазоне контрольных значений. Выводы. Отмечено значительное повышение фракций КЖК в кале у больных с хроническими запорами в начале наблюдения. Лечение комплексным препаратом Изиду привело к достоверному увеличению содержания масляной кислоты в кале (р &lt; 0,05), что имеет положительное прогностическое значение и свидетельствует об активизации защитных, детоксикационных и цитопротекторных эффектов.
Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study
Authors: Jamie L. Todd, Megan L. Neely, Heather Kopetskie, Michelle L. Sever, Jerry Kirchner, Courtney W. Frankel, Laurie D. Snyder, Elizabeth N. Pavlisko, Tereza Martinu, Wayne Tsuang, Michael Y. Shino, Nikki Williams, Mark A. Robien, Lianne G. Singer, Marie Budev, Pali D. Shah, John M. Reynolds, Scott M. Palmer, John A. Belperio, S. Sam Weigt
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction.Objectives: To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort.Methods: We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence.Measurements and Main Results: During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06; P ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57; P ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year.Conclusions: We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.
Electro-responsive films containing voltage responsive gated mesoporous silica nanoparticles grafted onto PEDOT-based conducting polymer
Authors: Alba García-Fernández, Beatriz Lozano-Torres, Juan F. Blandez, Javier Monreal-Trigo, Juan Soto, Jorge E. Collazos-Castro, Miguel Alcañiz, María D. Marcos, Félix Sancenón, Ramón Martínez-Máñez
Journal: Journal of Controlled Release (2020)
Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency
Authors: Maria Carmina Castiello, Marita Bosticardo, Nicolò Sacchetti, Enrica Calzoni, Elena Fontana, Yasuhiro Yamazaki, Elena Draghici, Cristina Corsino, Ileana Bortolomai, Lucia Sereni, Hsin-Hui Yu, Paolo Uva, Rahul Palchaudhuri, David T. Scadden, Anna Villa, Luigi D. Notarangelo
Journal: Journal of Allergy and Clinical Immunology (2020)

Mutations in the recombinase-activating genes cause severe immunodeficiency, with a spectrum of phenotypes ranging from severe combined immunodeficiency to immune dysregulation. Hematopoietic stem cell transplantation is the only curative option, but a high risk of graft failure and poor immune reconstitution have been observed in the absence of myeloablation.Our aim was to improve multilineage engraftment; we tested nongenotoxic conditioning with anti-CD45 mAbs conjugated with saporin CD45 (CD45-SAP).Rag1-KO and Rag1-F971L mice, which represent models of severe combined immune deficiency and combined immune deficiency with immune dysregulation, respectively, were conditioned with CD45-SAP, CD45-SAP plus 2 Gy of total body irradiation (TBI), 2 Gy of TBI, 8 Gy of TBI, or no conditioning and treated by using transplantation with lineage-negative bone marrow cells from wild-type mice. Flow cytometry and immunohistochemistry were used to assess engraftment and immune reconstitution. Antibody responses to 2,4,6-trinitrophenyl-conjugated keyhole limpet hemocyanin were measured by ELISA, and presence of autoantibody was detected by microarray.Conditioning with CD45-SAP enabled high levels of multilineage engraftment in both Rag1 mutant models, allowed overcoming of B- and T-cell differentiation blocks and thymic epithelial cell defects, and induced robust cellular and humoral immunity in the periphery.Conditioning with CD45-SAP allows multilineage engraftment and robust immune reconstitution in mice with either null or hypomorphic Rag mutations while preserving thymic epithelial cell homeostasis.
Long-Term Risk for Device-Related Complications and Reoperations After Implantable Cardioverter-Defibrillator Implantation
Authors: Isuru Ranasinghe, Craig S. Parzynski, James V. Freeman, Rachel P. Dreyer, Joseph S. Ross, Joseph G. Akar, Harlan M. Krumholz, Jeptha P. Curtis
Journal: Annals of Internal Medicine (2016)

Background: Long-term nonfatal outcomes after implantable cardioverter-defibrillator (ICD) placement are poorly defined. Objective: To determine the long-term risk for ICD-related complications requiring reoperation or hospitalization and reoperation for reasons other than complications, and to assess associated patient and device characteristics. Design: Observational cohort study of ICD implantations from the National Cardiovascular Data Registry ICD registry linked with Medicare fee-for-service claims data. Setting: 1437 U.S. hospitals. Patients: 114 484 patients aged 65 years or older (mean, 74.8 years [SD, 6.2]; 72.4% male) receiving an ICD for the first time from 2006 to 2010 (single-chamber, 19.8%; dual-chamber, 41.3%; cardiac resynchronization therapy with a defibrillator [CRT-D], 38.9%). Measurements: Rate and cumulative incidence of ICD-related complications requiring reoperation or hospitalization and reoperation for reasons other than complications. Results: During a median follow-up of 2.7 years (interquartile range, 1.8 to 3.9 years), 40 072 patients died, representing 12.6 (95% CI, 12.5 to 12.7) deaths per 100 patient-years of follow-up. When the risk for death was accounted for, there were 6.1 (CI, 6.0 to 6.2) ICD-related complications per 100 patient-years that required reoperation or hospitalization and 3.9 (CI, 3.8 to 4.0) reoperations per 100 patient-years for reasons other than complications. Overall, 10 patients had complications or reoperation per 100 patient-years of follow-up. Younger age at implantation (65 to 69 vs. >85 years) (hazard ratio [HR], 1.55 [CI, 1.43 to 1.69]), receipt of a CRT-D device (HR, 1.38 [CI, 1.31 to 1.45]) versus a single-chamber device, female sex (HR, 1.16 [CI, 1.12 to 1.21]), and black race (HR, 1.14 [CI, 1.05 to 1.23]) were associated with the greatest increased risks for ICD-related complications. Limitation: The analysis was limited to Medicare fee-for-service patients aged 65 years or older. Conclusion: Patients have a high rate of device-related complications and reoperation for other causes after ICD implantation. Risks of ICD implantation and strategies to reduce them should be actively considered before implantation. Primary Funding Source: American College of Cardiology Foundation's National Cardiovascular Data Registry.
The role of the microbiota in periodontal disease
Authors: Mike A. Curtis, Patricia I. Diaz, Thomas E. Van Dyke
Journal: Periodontology 2000 (2020)

Abstract The last decade has witnessed unparalleled advances in our understanding of the complexity of the oral microbiome and the compositional changes that occur in subgingival biofilms in the transition from health to gingivitis and to destructive periodontal disease. The traditional view, which has held sway for the last 2 decades, that disease is characterized by the outgrowth of a consortium, or consortia, of a limited number of potentially pathogenic organisms, has given way to an alternative paradigm. In this new view, the microbiological changes associated with disease represent whole‐scale alterations to the overall microbial population structure and to the functional properties of the entire community. Thus, and in common with other microbially mediated diseases of the gastrointestinal tract, the normally balanced, symbiotic, and generally benign commensal microbiome of the tooth‐associated biofilm undergoes dysbiosis to a potentially deleterious microbiota. Coincident with progress in defining the microbiology of these diseases, there have been equally important advances in our understanding of the inflammatory systems of the periodontal tissues, their control, and how inflammation may contribute both to the development of dysbiosis and, in a deregulated state, the destructive disease process. One can therefore speculate that the inflammatory response and the periodontal microbiome are in a bidirectional balance in oral health and a bidirectional imbalance in periodontitis. However, despite these clear insights into both sides of the host/microbe balance in periodontal disease, there remain several unresolved issues concerning the role of the microbiota in disease. These include, but are not limited to, the factors which determine progression from gingivitis to periodontitis in a proportion of the population, whether dysbiosis causes disease or results from disease, and the molecular details of the microbial stimulus responsible for driving the destructive inflammatory response. Further progress in resolving these issues may provide significant benefit to diagnosis, treatment, and prevention.
MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma
Authors: Victor H Engelhard, Rebecca C Obeng, Kara L Cummings, Gina R Petroni, Angela L Ambakhutwala, Kimberly A Chianese-Bullock, Kelly T Smith, Amanda Lulu, Nikole Varhegyi, Mark E Smolkin, Paisley Myers, Keira E Mahoney, Jeffrey Shabanowitz, Nico Buettner, Emily H Hall, Kathleen Haden, Mark Cobbold, Donald F Hunt, Geoffrey Weiss, Elizabeth Gaughan, Craig L Slingluff, Jr
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides. Methods Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3 126-134 ) was determined by 51 Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA–IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund’s adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay. Results pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3 126-134 controlled outgrowth of a tumor xenograft. The pIRS2 1097-1105 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3–4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS2 1097-1105 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3 126-134 peptide in 2/12 patients (17%, 90% CI 3% to 44%). Conclusion This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3 126-134 and pIRS2 1097-1105 , and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses. Trial registration number NCT01846143
2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data‐Driven Methodology Involving Three International Patient Cohorts
Authors: Caroline H. Shiboski, Stephen C. Shiboski, Raphaèle Seror, Lindsey A. Criswell, Marc Labetoulle, Thomas M. Lietman, Astrid Rasmussen, Hal Scofield, Claudio Vitali, Simon J. Bowman, Xavier Mariette
Journal: Arthritis & Rheumatology (2016)

Objective To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS. Methods We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi‐criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non‐SS controls, with case/non‐case status derived from expert clinical judgment. We then validated the performance of the classification criteria in a separate cohort of patients. Results The final classification criteria are based on the weighted sum of 5 items: anti‐SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm 2 , each scoring 3; an abnormal ocular staining score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 minutes, and an unstimulated salivary flow rate of ≤0.1 ml/minute, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician‐expert–derived case/non‐case status in the final validation cohort were high, i.e., 96% (95% confidence interval [95% CI] 92–98%) and 95% (95% CI 92–97%), respectively. Conclusion Using methodology consistent with other recent ACR/EULAR‐approved classification criteria, we developed a single set of data‐driven consensus classification criteria for primary SS, which performed well in validation analyses and are well‐suited as criteria for enrollment in clinical trials.
Long-term effects of cholecystectomy on bile acid metabolism*1, *2
Authors: G KULLAKUBLICK
Journal: Hepatology (1995)

Comparative studies between different patient groups have suggested that cholecystectomy enhances bacterial dehydroxylation of the primary bile acid cholic acid (CA) to the secondary bile acid deoxycholic acid (DCA). DCA may exert a cocarcinogenic effect on the colonic mucosa. In a short-term follow-up study on nine female patients we found no alterations of the CA or DCA pools after cholecystectomy. However, in the long term, cholecystectomy could promote changes of the intestinal bacterial flora and thereby lead to enhanced conversion of CA to DCA, causing an expansion of the DCA pool size and a reduction of the CA pool size. To test this hypothesis, pool sizes, fractional turnover rates (FTR), and synthesis or input rates of CA, chenodeoxycholic acid (CDCA) and DCA were determined in 12 female patients before and again 5 to 8 years after cholecystectomy. In the long term, pool size and synthesis rate of CA had not changed and DCA pool size had expanded by only 7.5% (not significant [NS]). DCA input increased by 32% (NS) but was balanced by an increase in FTR of 36%. Pool size (−17%) and synthesis rate (−5%) of CDCA were not significantly diminished. Overall, the sizes of the total bile acid pool (−6%, NS; 50 ± 8 vs. 53 ± 13 μmol/kg) and the pool fractions of CA (44.7 ± 10.3% vs. 42.8 ± 7.6%) and DCA (25.5 ± 14.1% vs. 23.6 ± 9.3%) remained similar. In conclusion, cholecystectomy causes no changes in bile acid pool composition and thus has no adverse effects on bile acid metabolism in the long term.