Diabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and ...peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.
The genomics data-driven identification of gene signatures and pathways has been routinely explored for predicting cancer survival and making decisions related to targeted treatments. A large number ...of packages and tools have been developed to correlate gene expression/mutations to the clinical outcome but lack the ability to perform such analysis based on pathways, gene sets, and gene ratios. Furthermore, in this single-cell omics era, the cluster markers from cancer single-cell transcriptomics studies remain an underutilized prognostic option. Additionally, no bioinformatics online tool evaluates the associations between the enrichment of canonical cell types and survival across cancers. Here we have developed Survival Genie, a web tool to perform survival analysis on single-cell RNA-seq (scRNA-seq) data and a variety of other molecular inputs such as gene sets, genes ratio, tumor-infiltrating immune cells proportion, gene expression profile scores, and tumor mutation burden. For a comprehensive analysis, Survival Genie contains 53 datasets of 27 distinct malignancies from 11 different cancer programs related to adult and pediatric cancers. Users can upload scRNA-seq data or gene sets and select a gene expression partitioning method (i.e., mean, median, quartile, cutp) to determine the effect of expression levels on survival outcomes. The tool provides comprehensive results including box plots of low and high-risk groups, Kaplan-Meier plots with univariate Cox proportional hazards model, and correlation of immune cell enrichment and molecular profile. The analytical options and comprehensive collection of cancer datasets make Survival Genie a unique resource to correlate gene sets, pathways, cellular enrichment, and single-cell signatures to clinical outcomes to assist in developing next-generation prognostic and therapeutic biomarkers. Survival Genie is open-source and available online at https://bbisr.shinyapps.winship.emory.edu/SurvivalGenie/ .
Age has historically been used to predict negative post-surgical outcomes. The concept of frailty was introduced to explain the discrepancies that exist between patients’ chronological and ...physiological age. The efficacy of the modified frailty index (mFI) to predict surgical risk is not clear.
We sought to synthesize the current literature to quantify the impact of frailty as a prognostic indicator across all surgical specialties.
Pubmed and Cochrane databases were screened from inception to 1 January 2018.
Studies utilizing the modified Frailty Index (mFI) as a post-operative indicator of any type of surgery. The mFI was selected based on a preliminary search showing it to be the most commonly applied index in surgical cohorts.
Articles were selected via a two-stage process undertaken by two reviewers (AP and DS). Statistical analysis was performed in Revman (Review manager V5.3). The random-effects model was used to calculate the Risk Ratios (RR).
The primary outcomes: post-operative complications, re-admission, re-operation, discharge to a skilled care facility, and mortality.
This meta-analysis of 16 studies randomizes 683,487 patients, 444,885 frail, from gastrointestinal, vascular, orthopedic, urogenital, head and neck, emergency, neurological, oncological, cardiothoracic, as well as general surgery cohorts. Frail patients were more likely to experience complications (RR 1.48, 95%CI 1.35–1.61; p < 0.001), major complications (RR 2.03, 95%CI 1.26–3.29; p = 0.004), and wound complications (RR 1.52, 95%CI 1.47–1.57; p < 0.001). Furthermore, frail patients had higher risk of readmission (RR 1.61, 95%CI 1.44–1.80; p < 0.001) and discharge to skilled care (RR 2.15, 95%CI 1.92–2.40; p < 0.001). Notably, the risk of mortality was 4.19 times more likely in frail patients (95% CI 2.96–5.92; p < 0.001).
and Relevance: This study is the first to synthesize the evidence across multiple surgical specialties and demonstrates that the mFI is an underappreciated prognostic indicator that strongly correlates with the risk of post-surgical morbidity and mortality. This supports that formal incorporation of pre-operative frailty assessment improves surgical decision-making.
•The mFI correlates with higher rates of post-operative complications, readmission, reoperation, and mortality.•Formal incorporation of preoperative frailty assessment using the mFI can improve surgical risk stratification.
Summary
This paper presents the design of a robust control law for a class of nonlinear dynamical systems subjected to parametric uncertainty and simultaneous unknown, variable state and input ...delays. A novel controller is developed, which consists of a filtered tracking error and the integral of previous values of control input where the limits of integration are dependent on the known bound of the input delay. Lyapunov‐Krasovskii functionals–based stability analysis guarantees a global uniformly ultimately bounded tracking result where sufficient conditions on controller gains and maximum allowable delay are derived. The performance and robustness of the controller are evaluated by simulation on a two‐link robot manipulator for different combinations of time‐varying state and input delays.
Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized ...that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.
The aim of the present study was to evaluate the effect of the application of calcium silicate materials (CSMs), after acid etching, on the longevity of the hybrid layer and marginal adaptation of ...composite restorations.
Eighty human permanent molars received an intrapulpal pressure of 15 cm H
O. Sixty teeth received a mesial proximal slot preparation with the gingival margin extending 1 mm below the cemento-enamel junction. The samples were divided into two groups. Group 1 received restorations using two types of etch-and-rinse adhesives: ethanol based (Single Bond, 3M ESPE, St Paul, MN, USA) and acetone based (Prime & Bond NT, Dentsply, DeTrey GmbH, Germany). In group 2 samples, a commercially available CSM (ProRoot MTA) was allowed to set before grinding and placing into a distilled water solution. This solution was applied on the cavity floor after acid etching. The surface was washed after 30 seconds followed by application of adhesives and restorations as in group 1. The samples were stored in phosphate-buffered saline for six months, maintaining the intrapulpal pressure. An epoxy replica was made, and the marginal adaptation was evaluated using scanning electron microscopy. The percentage of continuous margin (CM) was recorded for each group. Another 20 samples were used for hybrid layer evaluation. The crowns were ground to expose dentin. Intrapulpal pressure was applied. The samples were divided into two groups and restored similar to samples restored for marginal adaptation evaluation. The samples were longitudinally cut in 1-mm slices. The slices were stored under 15 cm of phosphate-buffered saline to simulate the pulpal pressure. After six months, the adhesive interface was evaluated using a scanning electron microscope. Statistical analysis was done with two-way analysis of variance with Holm-Sidak's correction for multiple comparisons.
Application of CSMs improved the marginal adaptation values in both adhesive groups. In group 1, there were areas of incomplete penetration of resins along with evidence of partial degradation of resin tags. Samples receiving CSM application after acid etching demonstrated long and regular resin tags with very few signs of degradation.
Application of CSMs after acid etching can be a potential avenue in preserving the resin-dentin bonds.
An online adaptive reinforcement learning-based solution is developed for the infinite-horizon optimal control problem for continuous-time uncertain nonlinear systems. A novel actor–critic–identifier ...(ACI) is proposed to approximate the Hamilton–Jacobi–Bellman equation using three neural network (NN) structures—actor and critic NNs approximate the optimal control and the optimal value function, respectively, and a robust dynamic neural network identifier asymptotically approximates the uncertain system dynamics. An advantage of using the ACI architecture is that learning by the actor, critic, and identifier is continuous and simultaneous, without requiring knowledge of system drift dynamics. Convergence of the algorithm is analyzed using Lyapunov-based adaptive control methods. A persistence of excitation condition is required to guarantee exponential convergence to a bounded region in the neighborhood of the optimal control and uniformly ultimately bounded (UUB) stability of the closed-loop system. Simulation results demonstrate the performance of the actor–critic–identifier method for approximate optimal control.
A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer ...cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.
For clinical studies of sarcopenia and frailty, clinically meaningful outcome measures are needed to monitor disease progression, evaluate efficacy of interventions, and plan clinical trials. ...Physical performance measures including measures of gait speed and other aspects of mobility and strength have been used in many studies, although a definition of clinically meaningful change in performance has remained unclear. The International Conference on Frailty and Sarcopenia Research Task Force (ICFSR-TF), a group of academic and industry scientists investigating frailty and sarcopenia, met in Miami Beach, Florida, USA in February 2019 to explore approaches for establishing clinical meaningfulness in a manner aligned with regulatory authorities. They concluded that clinical meaningful change is contextually dependent, and that both anchor- based and distribution-based methods of quantifying physical function are informative and should be evaluated relative to patient-reported outcomes. In addition, they identified additional research needed to enable setting criteria for clinical meaningful change in trials.
The Paris Agreement's success depends on parties' implementation of their Nationally Determined Contributions (NDCs) towards the Paris Agreement's goals. In these climate action plans, most ...developing countries make their mitigation and adaptation contributions conditional upon receiving international support (finance, technology transfer and/or capacity building). While provision of support for NDC implementation could enhance equity among countries, the feasibility of NDC implementation might be challenged by the large number of conditional NDCs. This paper addresses the implications of this tension based on an analysis of all 168 NDCs. We find that feasibility is challenged because conditions applied to NDCs are often not well defined. Moreover, the costs of implementing all conditional contributions are too high to be covered by existing promises of support from developed countries, even if the entire annual $100 billion of climate finance were earmarked for NDC implementation. Consistent with principles of equity and the prioritization in the Paris Agreement, a higher proportion of Least Developed Countries (LDCs) and Small Island Developing States (SIDS) have conditional NDCs than do other countries. However, differences between the distribution of countries requesting support and those currently receiving support, in particular among middle-income countries, demonstrates potential tensions between feasibility and equity. The article concludes with recommendations on how cost estimates and updated NDCs can be strengthened to ensure support for NDC implementation is targeted more equitably and cost-effectively.
Key policy insights
Support requested by developing countries to implement conditional NDCs far exceeds existing funding pledges.
Differences between existing patterns of financial assistance, and those implied by requests under conditional NDCs, mean that supporting NDCs may require a significant shift in provider countries' priorities for allocating climate finance. This may challenge feasibility.
The Paris Agreement's provisions on prioritizing LDCs and SIDS offer valuable guidance in making difficult choices on allocating support.
To increase the likelihood of attracting support, developing countries (assisted by capacity building as needed), should include credible cost estimates in future NDCs and formulate investment plans.
By outlining plans to mobilize support in their NDCs, developed countries can reassure developing countries that raising the ambition of NDCs is feasible.
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