Abstract Background The prevalence of adult obesity exceeds 30% in the United States, posing a significant public health concern as well as a substantial financial burden. Although the impact of ...obesity on medical spending is undeniably significant, the estimated magnitude of the cost of obesity has varied considerably, perhaps driven by different study methodologies. Objectives To document variations in study design and methodology in existing literature and to understand the impact of those variations on the estimated costs of obesity. Methods We conducted a systematic review of the twelve recently published articles that reported costs of obesity and performed a meta-analysis to generate a pooled estimate across those studies. Also, we performed an original analysis to understand the impact of different age groups, statistical models, and confounder adjustment on the magnitude of estimated costs using the nationally representative Medical Expenditure Panel Surveys from 2008-2010. Results We found significant variations among cost estimates in the existing literature. The meta-analysis found that the annual medical spending attributable to an obese individual was $1901 ($1239-$2582) in 2014 USD, accounting for $149.4 billion at the national level. The two most significant drivers of variability in the cost estimates were age groups and adjustment for obesity-related comorbid conditions. Conclusions It would be important to acknowledge variations in the magnitude of the medical cost of obesity driven by different study design and methodology. Researchers and policy-makers need to be cautious on determining appropriate cost estimates according to their scientific and political questions.
Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur ...within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.
Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.
In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.
The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.
ClinicalTrials.gov NCT01851733.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating ...electric fields to the tumor. OBJECTIVE: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. INTERVENTIONS: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). MAIN OUTCOMES AND MEASURES: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. RESULTS: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men 68%), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. CONCLUSIONS AND RELEVANCE: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409
SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic ...experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis.
In 2016, the American College of Cardiology published the first expert consensus decision pathway (ECDP) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in ...the management of atherosclerotic cardiovascular disease (ASCVD) risk. Since the publication of that document, additional evidence and perspectives have emerged from randomized clinical trials and other sources, particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in secondary prevention of ASCVD. Most notably, the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial and SPIRE-1 and -2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), assessing evolocumab and bococizumab, respectively, have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients. In addition, further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published. Based on results from these important analyses, the ECDP writing committee judged that it would be desirable to provide a focused update to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities. In the following summary table, changes from the 2016 ECDP to the 2017 ECDP Focused Update are highlighted, and a brief rationale is provided. The content of the full document has been changed accordingly, with more extensive and detailed guidance regarding decision making provided both in the text and in the updated algorithms. Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities on statin therapy for secondary prevention. The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C <190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes. Based on feedback and further deliberation, the ECDP writing committee down-graded recommendations regarding bile acid sequestrant use, recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe. For clarification, the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia, based on clinical criteria with and without genetic testing. Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians, unless there was a compelling reason or new evidence, in which case justification is provided.
Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD⁺). Nevertheless, how the regulation of this metabolic ...cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD⁺ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD⁺ levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD⁺-dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix–loop–helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD+ metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.
Subsequent independent guideline groups, including the 2014 Joint British Societies Consensus Recommendations for the Prevention of Cardiovascular Disease (JBS3) (3), the 2014 Veterans' ...Administration/Department of Defense Guidelines on Management of Dyslipidemia (4), and the recent U.S. Preventive Services Task Force draft recommendations (5), have used similar, rigorous approaches to reviewing and synthesizing evidence, resulting in similar treatment recommendations.\n Joseph Butterfield Chair in Pediatrics Sanofi-Aventis None None None None None Scott M. Grundy Content Reviewer--Chair, Update to ACC/AHA Cholesterol Guideline University of Texas Southwestern Medical Center at Dallas--Professor of Internal Medicine None None None None None None James L. Januzzi Content Reviewer--Chair, ACC Task Force on Clinical Expert Consensus Documents Massachusetts General Hospital--Director, Dennis and Marilyn Barry Fellowship in Cardiology Research Cardiology Division; Harvard Medical School--Hutter Family Professor of Medicine Novartislow * Rochelow * None None Amgen (DSMB) None None Joseph J. Saseen Content Reviewer--Cardiovascular Team Council University of Colorado Anschutz Medical Campus --Professor and Vice Chair, Department of Clinical Pharmacy, Professor, Department of Family Medicine None None None None None None Michael D. Shapiro Content Reviewer--Prevention Council Oregon Health & Science University--Associate Professor of Medicine and RadiologyDirector, Cardiac MR CT ProgramCenter for Preventive CardiologyKnight Cardiovascular Institute None None None Amarindagger Amgendagger Isisdagger Sanofidagger Synagevadagger None None Barbara S. Wiggins Content Reviewer--ACC Task Force on Clinical Expert Consensus Documents Medical University of South Carolina--Clinical Pharmacy Specialist Cardiology, Department of Pharmacy Services None None None None None None black square This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to this document.
SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes ...respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.
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•A hPSC-derived cell and organoid platform is used to study SARS-CoV-2 tissue tropism•Human pancreatic alpha and beta cells are permissive to SARS-CoV-2 infection•Human hepatocyte and cholangiocyte organoids are permissive to SARS-CoV-2 infection•hPSC-derived cells/organoids show similar chemokine responses as COVID-19 tissues
Yang et al. show that hPSC-derived cells and organoids provide valuable models to study SARS-CoV-2 tropism and to model COVID-19. They find that hPSC-derived pancreatic endocrine cells and human adult hepatocyte and cholangiocyte organoids are permissive to SARS-CoV-2 infection.
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