tbuckley/cabot-search huggingface dataset:
Assessment of common infections and incident dementia using UK primary and secondary care data: a historical cohort study
Authors: Rutendo Muzambi, Krishnan Bhaskaran, Liam Smeeth, Carol Brayne, Nish Chaturvedi, Charlotte Warren-Gash
Journal: The Lancet Healthy Longevity (2021)

Background Common infections have been associated with dementia risk; however, evidence is scarce .We aimed to investigate the association between common infections and dementia in adults (≥65 years) in a UK population-based cohort study. MethodsWe did a historical cohort study of individuals who were 65 years and older with no history of dementia or cognitive impairment using the Clinical Practice Research Datalink linked to Hospital Episode Statistics between Jan 1, 2004, and Dec 31, 2018.Multivariable Cox proportional hazard regression models were used to estimate the association between time-updated previous common infections (sepsis, pneumonia, other lower respiratory tract infections, urinary tract infections, and skin and soft tissue infections) and incident dementia diagnosis.We also tested for effect modification by diabetes since it is an independent risk factor for dementia and co-occurs with infection. FindingsBetween Jan 1, 2004, and Dec 31, 2018, our study included 989 800 individuals (median age 68•6 years [IQR 65•0-77•0]; 537 602 [54•3%] women) of whom 402 204 (40•6%) were diagnosed with at least one infection and 56 802 (5•7%) had incident dementia during a median follow-up of 5•2 years (IQR 2•3-9•0).Dementia risk increased in those with any infection (adjusted hazard ratio [HR] 1•53 [95% CI 1•50-1•55]) compared with those without infection.HRs were highest for sepsis (HR 2•08 [1•89-2•29]) and pneumonia (HR 1•88 [1•77-1•99]) and for infections leading to hospital admission (1•99 [1•94-2•04]).HRs were also higher in individuals with diabetes compared with those without diabetes.Interpretation Common infections, particularly those resulting in hospitalisation, were associated with an increased risk of dementia persisting over the long term.Whether reducing infections lowers the risk of subsequent dementia warrants evaluation.
Mutation Signatures of Pediatric Acute Myeloid Leukemia and Normal Blood Progenitors Associated with Differential Patient Outcomes
Authors: Arianne M. Brandsma, Eline J.M. Bertrums, Markus J. van Roosmalen, Damon A. Hofman, Rurika Oka, Mark Verheul, Freek Manders, Joske Ubels, Mirjam E. Belderbos, Ruben van Boxtel
Journal: Blood Cancer Discovery (2021)

Abstract Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults. Here we compare somatic mutations across pediatric acute myeloid leukemia (pAML) patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPC), as well as HSPCs from age-matched healthy donors. HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell of origin of the malignant blasts, suggesting polyclonal hematopoiesis in patients with pAML. Compared with normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize that these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable with age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML. Significance: Genome-wide analysis of pAML and patient-matched HSPCs provides new insights into the etiology of the disease and shows the clinical potential of these analyses for patient stratification. This article is highlighted in the In This Issue feature, p. 403
Prediction of Clinically Relevant Mutations in (MDS): A Report on Behalf of the MDS Clinical Research Consortium (CRC)
Authors: Sangmin Lee, John Barnard, Rami S. Komrokji, Amy E. DeZern, David P. Steensma, Jaroslaw P. Maciejewski, Ellen K Ritchie, Pinkal Desai, Felix Tavernier, Duane C. Hassane, Guillermo Garcia-Manero, Mikkael A. Sekeres, Gail J. Roboz
Journal: Blood (2017)
Comparative efficacy of calcipotriol (MC903) cream and betamethasone 17-valerate cream in the treatment of chronic plaque psoriasis. A randomized, double-blind, parallel group multicentre study
Authors: L Molin, T P Cutler, I Helander, B Nyfors, N Downes
Journal: British Journal of Dermatology (1997)

The efficacy, safety and tolerability of calcipotriol cream was compared with betamethasone 17-valerate cream in the treatment of plaque-type psoriasis in a multicentre double-blind, parallel group study. Patients with stable mild-to-moderate chronic disease were randomized to treatment with either calcipotriol, 50 micrograms/g, in a cream formulation (210 patients) or betamethasone 17-valerate cream, 1 mg/g (211 patients). After a wash-out period of 2 weeks, the treatment was applied twice daily, without occlusion, for 8 weeks or to complete clearing. The severity of psoriasis was assessed using the PASI at baseline and after 4 and 8 weeks treatment. The mean percentage reduction of PASI from baseline to end of treatment was 47.8% in the calcipotriol group and 45.4% in the betamethasone group. The reduction from baseline was highly significant in both groups, but the difference between the groups was not significant. There was a difference in the reduction in thickness of the lesions in favour of calcipotriol. The investigator's as well as the patient's overall assessment of treatment response at end of treatment showed no difference between the two treatment groups. Treatment-related adverse events were more frequent with calcipotriol than betamethasone. Lesional/perilesional irritation was reported in 16% and 9% (P = 0.03), and facial irritation in 10% and 0.5% (P < 0.001), respectively. No change was found in serum levels of calcium. Calcipotriol in a cream formulation was effective, safe, well-tolerated, and equal in effect to betamethasone valerate cream.
Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction
Authors: Andreas Mangold, Anna S Ondracek, Thomas M Hofbauer, Thomas Scherz, Tyler Artner, Noel Panagiotides, Dietrich Beitzke, Gerhard Ruzicka, Sonja Nistler, Evelyne Wohlschläger-Krenn, Robert Winker, Peter Quehenberger, Denise Traxler-Weidenauer, Andreas Spannbauer, Mariann Gyöngyösi, Christoph Testori, Irene M Lang
Journal: Cardiovascular Research (2021)

Abstract Aims Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation, and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST-elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin, and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints. Methods and results In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin, and inflammation were measured. Double-stranded deoxyribonucleic acid (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase, and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF. In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients. Conclusions NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.
Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial
Authors: Samuel T. Wilkinson, Taeho Greg Rhee, Jutta Joormann, Ryan Webler, Mayra Ortiz Lopez, Brandon Kitay, Madonna Fasula, Christina Elder, Lisa Fenton, Gerard Sanacora
Journal: Psychotherapy and Psychosomatics (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen &lt;i&gt;d&lt;/i&gt; = 0.65; 95% CI –0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (&lt;i&gt;F&lt;/i&gt; = 4.58; &lt;i&gt;p&lt;/i&gt; = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen &lt;i&gt;d&lt;/i&gt; = 0.71 (95% CI –0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (&lt;i&gt;N&lt;/i&gt; = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (&lt;i&gt;t&lt;/i&gt;[8] = 2.33; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05) whereas nonresponders did not (&lt;i&gt;t&lt;/i&gt;[10] &amp;#x3c;1; &lt;i&gt;p&lt;/i&gt; ns). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.
DDIS-15. SYNERGISTIC INHIBITION OF GLIOMA CELL PROLIFERATION BY WITHAFERIN A AND TUMOR TREATING FIELDS
Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag B Patel, Jarrett Rosenberg, Dong Ho Ha, Sanjiv S Gambhir
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain cancer. Standard therapies are non-specific and often of limited effectiveness; thus, efforts are underway to uncover novel, unorthodox therapies against GBM. In previous studies, we investigated Withaferin A, a steroidal lactone from Ayurvedic medicine that inhibits proliferation in cancers including GBM. Another novel approach, tumor treating fields (TTFields), is thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cells. We hypothesized that combining TTFields with Withaferin A would synergistically inhibit proliferation in glioblastoma. Human glioblastoma cells (GBM2, GBM39, U87-MG) and human breast adenocarcinoma cells (MDA-MB-231) were isolated from primary tumors. The glioma cell lines were genetically engineered to express firefly luciferase. Proliferative potential was assessed either by bioluminescence imaging or cell counting via hemocytometer. TTFields (4 V/cm) significantly inhibited growth of the four cancer cell lines tested (n=3 experiments per time point, 4 measurements per sample, p<0.02 at least; 2-way ANOVA, control vs. treatment). The combination of Withaferin A (10–100 nM) with TTFields significantly inhibited the growth of the glioma cells to a degree beyond that of Withaferin A or TTFields alone. The interaction of the Withaferin A and TTFields on glioma cells was found to be synergistic in nature (p<0.01, n=3 experiments). These findings were validated by both bioluminescence and hemocytometric measurements. The combination of Withaferin A with TTFields represents a novel approach to treat GBM in a manner that is likely better than either treatment alone and that is synergistic.
Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans
Authors: Jiwon Jung, Sophia T. Mundle, Irina V. Ustyugova, Andrew P. Horton, Daniel R. Boutz, Svetlana Pougatcheva, Ponraj Prabakaran, Jonathan R. McDaniel, Gregory R. King, Daechan Park, Maria D. Person, Congxi Ye, Bing Tan, Yuri Tanno, Jin Eyun Kim, Nicholas C. Curtis, Joshua DiNapoli, Simon Delagrave, Ted M. Ross, Gregory C. Ippolito, Harry Kleanthous, Jiwon Lee, George Georgiou
Journal: Journal of Clinical Investigation (2021)

Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.
Abstract 339: Quality of Physician Care Coordination During Inter-Facility Transfer for Cardiac Arrest Patients
Authors: Stephen N Holby, Daniel Munoz, Sean P Collins, Timothy J Vogus, Cathy A Jenkins, Dandan Liu, Michael J Ward
Journal: Circulation (2019)

Objectives: We sought to evaluate whether the quality of coordination between physicians transferring comatose cardiac arrest survivors to a high-volume cardiac arrest center for targeted temperature management (TTM) was associated with timeliness of care. Methods: We conducted a retrospective analysis of inter-facility transfers to Vanderbilt University Medical Center for TTM between October 2016 and October 2018. We examined the relationship between Relational Coordination (RC) - a validated measure comprised of 7 dimensions of communication (frequency, timeliness, accuracy, problem solving) and relationship quality (respect, knowledge sharing, shared goals) - during recorded phone conversations between transferring and accepting physicians and time-to-acceptance. Investigators listened to recorded phone conversations and used a scoring guide to assign a score between 1 and 100 for each of the 7 dimensions of RC. Results: We identified 18 patients meeting criteria. TTM was initiated or continued in 72% (13 of 18). Median time-to-acceptance was 2.77 (interquartile range [IQR] 2.0, 4.1) minutes, and duration of calls was 3.95 (IQR 2.7, 5.2) minutes. Inter-rater reliability for overall RC was high (rho=0.87). The correlation between RC and the time-to-acceptance was significant in univariate analyses (adjusted relative risk=0.96, 95%CI 0.93, 1.0, p=0.05). Secondary analyses did not find a significant relationship between RC and timeliness measures. Conclusions: In this sample of patients transferred for TTM, we found that RC had a high inter-rater reliability. We also found that higher quality care coordination for cardiac arrest survivors was associated with faster physician acceptance. To better understand how the quality of care coordination impacts timeliness of care and patient outcomes, future work using a larger cohort should examine whether higher RC among a broader set of stakeholders (physicians, emergency medical services, families, etc.) is associated with timeliness measures after adjusting for other factors.
Crucial Role of miR-433 in Regulating Cardiac Fibrosis: Erratum
Authors: Lichan Tao, Yihua Bei, Ping Chen, Zhiyong Lei, Siyi Fu, Haifeng Zhang, Jiahong Xu, Lin Che, Xiongwen Chen, Joost PG Sluijter, Saumya Das, Dragos Cretoiu, Bin Xu, Jiuchang Zhong, Junjie Xiao, Xinli Li
Journal: Theranostics (2021)
Abstract 279: Stromal Cell-derived Factor-1 Prevents From Diabetic Cardiomyopathy via Cxcr7/ampk-mediated Nrf2 Activation in Type 2 Diabetic Mice
Authors: Shudong Wang, Junlian Gu, Xiaoqing Yan, Jing Chen, Jun Chen, Lu Cai, Quan Liu, Yang Zheng, Yi Tan
Journal: Circulation Research (2016)

We have demonstrated that stromal cell-derived factor 1(SDF-1) protects against palmitate-induced cardiac cell death via CXCR7-mediated activation of AMPK signaling (Diabetes 62:2545-2558, 2013). Whether SDF-1 prevents diabetic cardiomyopathy (DCM) and what the underlying mechanism has not been addressed. Here we evaluated the prevention of SDF-1 from DCM in a high fat diet plus streptozotocin (HFD/STZ)-induced type 2 diabetic model in C57BL/6J mice. After 1 month on HFD, the HFD-fed mice were injected with one low dose STZ (100mg/kg body weight, ip). Five days after STZ injection, mice with blood glucose levels ≥250 mg/dl were defined as diabetic. In parallel, the age-matched normal diet-fed mice injected with a same volume of vehicle were used as control. After onset of diabetes, the mice were maintained on HFD or normal diet for another 4 months with or without SDF-1 treatment. Then cardiac function was assayed again, and the mice were sacrificed and cardiac tissue collected for cardiomyopathic index assay. We found that 1 month HFD feeding induced a significant insulin resistance without effect on cardiac function, but continued HFD feeding after STZ injection significantly increased insulin resistance and blood glucose, as well as blood insulin, triglyceride and cholesterol levels. Furthermore, HFD/STZT significantly impaired cardiac function, which were accompanied by increased cardiac inflammation, oxidative stress and fibrotic remodeling. Treatment with SDF-1 dose-dependently prevented diabetes-induced cardiac dysfunction, inflammation and remodeling, but without significant effects on the above mentioned other pathophysiological changes. Mechanistic study demonstrated that diabetes significantly inhibited the function of AMPK and Nrf2, and the expression of CXCR7, but not CXCR4; while treatment with SDF-1 significantly preserved AMPK and Nrf2 function and CXCR7 expression. Knockout CXCR4 did not affect SDF-1 preservation of AMPK and Nrf2 function, but SiRNA knockdown of AMPK resulted in blockade of SDF-1 preservation of Nrf2 function. These results indicate that SDF-1 prevents from DCM via CXCR7/AMPK-mediated Nrf2 activation in type 2 diabetic mice.
Angiosome Based Below-the-Knee (BK) Endovascular Treatment (EVT) for Wound Critical Ischemic Limbs (CLI) Affect the Healing Time of Wounds
Authors: Yamauchi Yasutaka, Miyamoto Akira, Hakamata Naohiro, Fukuda Masahiro, Akita Takako, Kuhara Ryoji, Tezuka Shingo, Shiigai Masaru
Journal: Circulation (2014)
Recapitulation of Thymic Function by Tissue Engineering Strategies
Authors: Catarina S. Silva, Rui L. Reis, Albino Martins, Nuno M. Neves
Journal: Advanced Healthcare Materials (2021)

Abstract The thymus is responsible for the development and selection of T lymphocytes, which in turn also participate in the maturation of thymic epithelial cells. These events occur through the close interactions between hematopoietic stem cells and developing thymocytes with the thymic stromal cells within an intricate 3D network. The complex thymic microenvironment and function, and the current therapies to induce thymic regeneration or to overcome the lack of a functional thymus are herein reviewed. The recapitulation of the thymic function using tissue engineering strategies has been explored as a way to control the body's tolerance to external grafts and to generate ex vivo T cells for transplantation. In this review, the main advances in the thymus tissue engineering field are disclosed, including both scaffold‐ and cell‐based strategies. In light of the current gaps and limitations of the developed systems, the design of novel biomaterials for this purpose with unique features is also discussed.
Assessment of FDA Approval for New High-risk Therapeutic Devices Not Meeting Pivotal Study Primary End Points, 2016-2020
Authors: James L. Johnston, Sanket S. Dhruva, Joseph S. Ross, Vinay K. Rathi
Journal: JAMA Internal Medicine (2021)

This cross-sectional study explores the frequency of, and rationale for, US Food and Drug Administration approval of high-risk therapeutic medical devices not meeting pivotal study primary end points from 2016 through 2020.