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.
Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an ...unusual anti-angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsis-specific treatment.
Background: Gingival augmentation procedures around natural teeth and dental implants are performed to facilitate plaque control, to improve patient comfort, to prevent future recession, and in ...conjunction with restorative, orthodontic, or prosthetic dentistry. The aim of this study is to answer the most common questions related to this treatment modality based on the most relevant and current knowledge in the field.
Methods: Two reviewers worked to answer the five most common and clinically relevant questions with supporting literature to understand the role of gingiva around teeth. 1) What circumstances require an increased zone of keratinized tissue (KT), or is KT important? 2) What is the ideal thickness of an autogenous gingival graft? Is a thick autogenous gingival graft more effective than a thin autogenous gingival graft? 3) What are the alternatives to autogenous gingival grafting to increase the zone of attached gingiva? 4) Does orthodontic intervention affect soft tissue health and dimensions? 5) What is the patient‐reported patient outcome for minimal KT compared with that for an enhanced zone of KT? An extensive literature search was performed using PubMed, the Cochrane Oral Health Group Specialized Trials Registry (the Cochrane Library), and the most respected journals in the field.
Results: Although gingival augmentation procedures were first introduced in 1960s, there have not been in‐depth comparative studies examining the five questions that have been proposed by the authors. Lack of relevant systematic reviews and randomized clinical trials (RCTs) on this topic do not allow authors to answer those questions with a strong level of evidence. However, the following can be recommended after reviewing case reports and case series on these topics. 1) There is enough clinical evidence to support maintaining an adequate band of gingiva for intracrevicular margin restoration. 2) Thick grafts do not appear to result in better clinical outcomes than thin grafts. Thick grafts are likely to result in more primary contraction, whereas thin grafts tend to be prone to secondary contraction. 3) Viable alternative treatment modalities are currently available that are capable of providing KT augmentation without the need for palatal donor tissue. 4) Appropriately applied orthodontic forces do not cause permanent damage to a healthy periodontium. The probability of recession during tooth movement in thin biotype is high to justify gingival augmentation when the dimension of gingiva is inadequate. In addition, cases in which there will be a facial tooth movement outside of the alveolar process need to be considered for a gingival augmentation procedure. 5) Although the articles that have been published on this topic did not consider patient‐reported outcomes and esthetics as part of the overall treatment success assessment, patients who have received alternative treatment modalities that did not depend on palatal tissue harvesting appear to have reported more satisfaction and less discomfort after treatment.
Conclusions: Autogenous gingival grafts are still considered to be the “gold standard” procedure with unmatched success rates and clinical success when gingival augmentation procedures are required. However, tissue‐engineered materials may offer viable options to palatal tissue harvesting for gingival augmentation. KT augmentation may prevent the development and progression of gingival recession, especially when restorative margins may interact with the periodontium and/or orthodontic treatment is indicated. Patient‐reported outcomes should be considered for future studies on this topic. Additional RCTs and systematic reviews are needed to support these conclusions.
Many naturally occurring protein systems function primarily as symmetric assemblies. Prediction of the quaternary structure of these assemblies is an important biological problem. This article ...describes automated tools we have developed for predicting the structures of symmetric protein assemblies in the Robetta structure prediction server. We assess the performance of this pipeline on a set of targets from the recent CASP12/CAPRI blind quaternary structure prediction experiment. Our approach successfully predicted 5 of 7 symmetric assemblies in this challenge, and was assessed as the best participating server group, and 1 of only 2 groups (human or server) with 2 predictions judged as high quality by the assessors. We also assess the method on a broader set of 22 natively symmetric CASP12 targets, where we show that oligomeric modeling can improve the accuracy of monomeric structure determination, particularly in highly intertwined oligomers.
Despite decades of work by structural biologists, there are still ~5200 protein families with unknown structure outside the range of comparative modeling. We show that Rosetta structure prediction ...guided by residue-residue contacts inferred from evolutionary information can accurately model proteins that belong to large families and that metagenome sequence data more than triple the number of protein families with sufficient sequences for accurate modeling. We then integrate metagenome data, contact-based structure matching, and Rosetta structure calculations to generate models for 614 protein families with currently unknown structures; 206 are membrane proteins and 137 have folds not represented in the Protein Data Bank. This approach provides the representative models for large protein families originally envisioned as the goal of the Protein Structure Initiative at a fraction of the cost.
Attention deficit hyperactivity disorder (ADHD) and glioblastoma multiforme (GBM) are two neurological disorders with high rates of incidence and mortality respectively, both capable of inflicting ...long‐term physiological damage. Although prior research has indicated that brain tumor survivors exhibit increases in susceptibility to ADHD, the underlying genetic components still remain relatively unknown. The primary purpose of this investigation was to identify genetic associations between ADHD and GBM by single‐nucleotide polymorphisms (SNPs) of target genes. NCBI’s Gene Expression Omnibus was accessed, and genes of interest were selected by differential gene expression analysis in GBM patients. Sequence data of ADHD and GBM patients were obtained from the Sequence Read Archive (SRA), followed by the construction of analysis pipelines to map the sequences against human chromosome 12, followed by indexing and variant calling. This study highlights 18 variants (including 7 reported SNPs) that contribute to the genetic overlap of ADHD and GBM and may provide a useful tool for precision medicine.
We describe several notable aspects of our structure predictions using Rosetta in CASP12 in the free modeling (FM) and refinement (TR) categories. First, we had previously generated (and published) ...models for most large protein families lacking experimentally determined structures using Rosetta guided by co‐evolution based contact predictions, and for several targets these models proved better starting points for comparative modeling than any known crystal structure—our model database thus starts to fulfill one of the goals of the original protein structure initiative. Second, while our “human” group simply submitted ROBETTA models for most targets, for six targets expert intervention improved predictions considerably; the largest improvement was for T0886 where we correctly parsed two discontinuous domains guided by predicted contact maps to accurately identify a structural homolog of the same fold. Third, Rosetta all atom refinement followed by MD simulations led to consistent but small improvements when starting models were close to the native structure, and larger but less consistent improvements when starting models were further away.
Most biomolecular modeling energy functions for structure prediction, sequence design, and molecular docking have been parametrized using existing macromolecular structural data; this contrasts ...molecular mechanics force fields which are largely optimized using small-molecule data. In this study, we describe an integrated method that enables optimization of a biomolecular modeling energy function simultaneously against small-molecule thermodynamic data and high-resolution macromolecular structural data. We use this approach to develop a next-generation Rosetta energy function that utilizes a new anisotropic implicit solvation model, and an improved electrostatics and Lennard-Jones model, illustrating how energy functions can be considerably improved in their ability to describe large-scale energy landscapes by incorporating both small-molecule and macromolecule data. The energy function improves performance in a wide range of protein structure prediction challenges, including monomeric structure prediction, protein-protein and protein-ligand docking, protein sequence design, and prediction of the free energy changes by mutation, while reasonably recapitulating small-molecule thermodynamic properties.
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