Concurrent Optical- and Magnetic-Stimulation-Induced Changes on Wound Healing Parameters, Analyzed by Hyperspectral Imaging: An Exploratory Case Series.

The effects of concurrent optical and magnetic stimulation (COMS) therapy on wound-healing-related parameters, such as tissue oxygenation and water index, were analyzed by hyperspectral imaging: an exploratory case series. Background: Oedema and inadequate perfusion have been identified as key factors in delayed wound healing and have been linked to reduced mitochondrial respiration. Targeting mitochondrial dysfunction is a promising approach in the treatment of therapy refractory wounds. This sub-study aimed to investigate the effects of concurrent optical and magnetic stimulation (COMS) on oedema and perfusion through measuring tissue oxygenation and water index, using hyperspectral imaging. Patients and methods: In a multi-center, prospective, comparative clinical trial, eleven patients with chronic leg and foot ulcers were treated with COMS additively to Standard of Care (SOC). Hyperspectral images were collected during patient visits before and after treatment to assess short- and long-term hemodynamic and immunomodulatory effects through changes in tissue oxygenation and water index. Results: The average time for wound onset in the eleven patients analyzed was 183 days, with 64% of them being considered unresponsive to SOC. At week 12, the rate of near-complete and complete wound closure was 64% and 45%, respectively. COMS therapy with SOC resulted in an increased short-term tissue oxygenation over the 8-week treatment phase, with oxygen levels decreasing in-between patient visits. The study further found a decrease in tissue water content after the therapy, with a general accumulation of water levels in-between patient visits. This study's long-term analysis was hindered by the lack of absolute values in hyperspectral imaging and the dynamic nature of patient parameters during visits, resulting in high interpatient and intervisit variability. Conclusions: This study showed that COMS therapy as an adjunct to SOC had a positive short-term effect on inflammation and tissue oxygenation in chronic wounds of various etiologies. These results further supported the body of evidence for safety and effectiveness of COMS therapy as a treatment option, especially for stagnant wounds that tended to stay in the inflammatory phase and required efficient phase transition towards healing.

Global monthly sectoral water use for 2010-2100 at 0.5° resolution across alternative futures.

Water usage is closely linked with societal goals that are both local and global in scale, such as sustainable development and economic growth. It is therefore of value, particularly for long-term planning, to understand how future sectoral water usage could evolve on a global scale at fine resolution. Additionally, future water usage could be strongly shaped by global forces, such as socioeconomic and climate change, and the multi-sector dynamic interactions those forces create. We generate a novel global gridded monthly sectoral water withdrawal and consumption dataset at 0.5° resolution for 2010-2100 for a diverse range of 75 scenarios. The scenarios are harmonized with the five Shared Socioeconomic Pathways (SSPs) and four Representative Concentration Pathways (RCPs) scenarios to support its usage in studies evaluating the implications of uncertain human and earth system change for future global and regional dynamics. To generate the data, we couple the Global Change Analysis Model (GCAM) with a land use spatial downscaling model (Demeter), a global hydrologic framework (Xanthos), and a water withdrawal downscaling model (Tethys).

Extracorporeal therapy of sepsis by purified granulocyte concentrates: ex vivo circulation model.

BACKGROUND: Immune cell dysfunction is a central part of immune paralysis in sepsis. Granulocyte concentrate (GC) transfusions can induce tissue damage via local effects of neutrophils. The hypothesis of an extracorporeal plasma treatment with granulocytes is to show beneficial effects with fewer side effects. Clinical trials with standard GC have supported this approach. This ex vivo study investigated the functional properties of purified granulocyte preparations during the extracorporeal plasma treatment. METHODS: Purified GC were stored for up to 3 days and compared with standard GC in an immune cell perfusion therapy model. The therapy consists of a plasma separation device and an extracorporeal circuit. Plasma is perfused through the tubing system with donor immune cells of the GC, and only the treated plasma is filtered for re-transfusion. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Efficacy of granulocytes regarding phagocytosis, oxidative burst as well as cell viability and metabolic parameters were assessed. RESULTS: In pGC, the metabolic surrogate parameters of cell functionality showed comparable courses even after a storage period of 72 h. In particular, glucose and oxygen consumption were lower after extended storage. The course of lactate dehydrogenase concentration yields no indication of cell impairment in the extracorporeal circulation. The cells were viable throughout the entire study period and exhibited preserved phagocytosis and oxidative burst functionality. CONCLUSION: The granulocytes demonstrated full functionality in the 6 h extracorporeal circuits after 3 days storage and in septic shock plasma. This is demonstrating the functionality of the system and encourages further clinical studies.

Topical autologous blood clot therapy: consensus panel recommendations to guide use in the treatment of complex wound types.

The etiology of acute and chronic wounds goes beyond those often reported in the literature, including those with exposed structures, those in which the entire wound bed cannot be visualized, and patients who are not candidates for typical standard of care. Treatment options for these patients may be limited. TABCT is a viable option for these complex wound types and is not hindered by logistical, procedural, or patient factors. A consensus panel of providers with extensive experience in treatment of these wound types was convened to develop consensus recommendations on the use of TABCT in specific complex wound types. Four consensus statements were defined for TABCT use in patients who cannot undergo sharp or extensive debridement, as a protective barrier to prevent further bacterial ingress, in patients with wounds in which the entire wound bed cannot be safely visualized, and in wounds with exposed tendon and/or bone. Consensus panel recommendations show that TABCT application assists in maintenance of a moist wound healing environment, autolytic debridement, recruitment and delivery of factors essential for wound healing, prevention of pathogen entry, and ability to completely fill wound voids that cannot be fully visualized. Additional advantages of TABCT use are its cost-effectiveness, ease of access, minimal related complications, and proven clinical efficacy.

Topical autologous blood clot therapy: an introduction and development of consensus panel to guide use in the treatment of complex wound types.

Complex or hard-to-heal wounds can be acute or chronic; the complexity is based on patient-specific local, systemic, and psychosocial factors. Use of autologous tissue can be a significant adjunct to wound closure. Grafts and flaps are the most common autologous tissue used in wound reconstruction. However, patient factors, wound size, and exposed structures may preclude using these methods as primary or even secondary closure techniques. Alternative autologous tissue therapies include those derived from adipose, epidermis or dermis, bone marrow, and blood. Limitations of these treatment modalities include access-related difficulty, cost, creation of a secondary donor site, use of singular or limited cell types, and sparse or contradictory evidence basis of their efficacy of use. A panel of providers experienced in wound care and surgical wound management was convened to create a series of publications on the use of topical autologous blood clot therapy (TABCT) in the treatment of complex wounds. This publication, the first in a series, provides an evidence basis of the gap between definition and treatment of complex wounds, an overview of the use of autologous therapies in these wounds, and the science behind TABCT. The development of a consensus panel for decision pathways and recommendations for TABCT use in specific complex wound types are also discussed. Subsequent articles will provide consensus recommendations on the use of TABCT in full-thickness wounds with exposed tendon and/or bone and undermining or tunneling wounds, in wounds in patients who are nonsurgical candidates, in those who cannot undergo sharp debridement, in patients with arterial wounds who have been maximally revascularized, and in those with transsphincteric anal fistula. This article provides a foundation of knowledge and describes the plan for consensus panel decision pathways and recommendation development of use of TABCT in the treatment of specific complex wound types.

Extracorporeal immune cell therapy of sepsis: ex vivo results.

BACKGROUND: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. The transfusion of healthy donor immune cells, i.e., granulocyte concentrates (GC) potentially induces tissue damage via local effects of neutrophils. Initial clinical trials using standard donor GC in a strictly extracorporeal bioreactor system for treatment of septic shock patients already provided evidence for beneficial effects with fewer side effects, by separating patient and donor immune cells using plasma filters. In this ex vivo study, we demonstrate the functional characteristics of a simplified extracorporeal therapy system using purified granulocyte preparations. METHODS: Purified GC were used in an immune cell perfusion model prefilled with human donor plasma simulating a 6-h treatment. The extracorporeal circuit consisted of a blood circuit and a plasma circuit with 3 plasma filters (PF). PF1 is separating the plasma from the patient's blood. Plasma is then perfused through PF2 containing donor immune cells and used in a dead-end mode. The filtrated plasma is finally retransfused to the blood circuit. PF3 is included in the plasma backflow as a redundant safety measure. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Phagocytosis activity, oxidative burst and cell viability as well as cytokine release and metabolic parameters of purified GCs were assessed. RESULTS: Cells were viable throughout the study period and exhibited well-preserved functionality and efficient metabolic activity. Course of lactate dehydrogenase and free hemoglobin concentration yielded no indication of cell impairment. The capability of the cells to secret various cytokines was preserved. Of particular interest is equivalence in performance of the cells on day 1 and day 3, demonstrating the sustained shelf life and performance of the immune cells in the purified GCs. CONCLUSION: Results demonstrate the suitability of a simplified extracorporeal system. Furthermore, granulocytes remain viable and highly active during a 6-h treatment even after storage for 3 days supporting the treatment of septic patients with this system in advanced clinical trials.

Analysis of the Influence of Surface Modifications on the Fatigue Behavior of Hot Work Tool Steel Components.

Hot work tool steels (HWS) are widely used for high performance components as dies and molds in hot forging processes, where extreme process-related mechanical and thermal loads limit tool life. With the functionalizing and modification of tool surfaces with tailored surfaces, a promising approach is given to provide material flow control resulting in the efficient die filling of cavities while reducing the process forces. In terms of fatigue properties, the influence of surface modifications on surface integrity is insufficiently studied. Therefore, the potential of the machining processes of high-feed milling, micromilling and grinding with regard to the implications on the fatigue strength of components made of HWS (AISI H11) hardened to 50 ± 1 HRC was investigated. For this purpose, the machined surfaces were characterized in terms of surface topography and residual stress state to determine the surface integrity. In order to analyze the resulting fatigue behavior as a result of the machining processes, a rotating bending test was performed. The fracture surfaces were investigated using fractographic analysis to define the initiation area and to identify the source of failure. The investigations showed a significant influence of the machining-induced surface integrity and, in particular, the induced residual stress state on the fatigue properties of components made of HWS.

Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol).

BACKGROUND: A venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines. AIM: The aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration. METHODS: Through a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.

Power sector investment implications of climate impacts on renewable resources in Latin America and the Caribbean.

Climate change mitigation will require substantial investments in renewables. In addition, climate change will affect future renewable supply and hence, power sector investment requirements. We study the implications of climate impacts on renewables for power sector investments under deep decarbonization using a global integrated assessment model. We focus on Latin American and Caribbean, an under-studied region but of great interest due to its strong role in international climate mitigation and vulnerability to climate change. We find that accounting for climate impacts on renewables results in significant additional investments ($12-114 billion by 2100 across Latin American countries) for a region with weak financial infrastructure. We also demonstrate that accounting for climate impacts only on hydropower-a primary focus of previous studies-significantly underestimates cumulative investments, particularly in scenarios with high intermittent renewable deployment. Our study underscores the importance of comprehensive analyses of climate impacts on renewables for improved energy planning.

Unusual Manifestation of Chronic Lymphocytic Leukemia in the Hand.

Chronic lymphocytic leukemia (CLL) involving the hand, especially with bone involvement, is extremely rare. We report a case of a 62-year-old man, with a 4-year history of a subclinical CLL, presenting with chronic swelling and pain over the dorsal surface of the right hand, mimicking an infectious process. There was no clinical response to broad-spectrum antibiotics and topical corticosteroid therapy. Imaging was inconclusive. A tissue biopsy revealed a manifestation of the underlying leukemia. This case highlights the need to consider uncommon etiologies for atypical clinical presentations.

3D-perfusion analysis of burn wounds using hyperspectral imaging.

BACKGROUND: Determination of the depth of burn wounds is still a challenge in clinical practise and fundamental for an optimal treatment. Hyperspectral imaging (HSI) has a high potential to be established as a new contact-free measuring method in medicine. From hyperspectral spectra 3D-perfusion parameters can be estimated and the microcirculatory of burn wounds over the first 72h after thermal injury can be objectively described. METHODS: We used a hyperspectral imaging camera and extended data processing methods to calculate 3D-perfusion parameters of burn wounds from adult patients. The data processing results in the estimation of perfusion parameters like volume fraction and oxygenation of haemoglobin for 6 different layers of the injured skin. The parameters are presented as depth profiles. We analyzed and compared measurements of wounds of different degrees of damage and present the methodology and preliminary results. RESULTS: The depth profiles of the perfusion parameters show characteristic features and differences depending on the degree of damage. With Hyperspectral Imaging and the advanced data processing the perfusion characteristics of burn wounds can be visualized in more detail. Based on the analysis of this perfusion characteristics, a new and better reliable classification of burn degrees can be developed supporting the surgeon in the early selection of the optimal treatment.

A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study.

OBJECTIVE: Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone. RESEARCH DESIGN AND METHODS: Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapy-both in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase. RESULTS: At the first analysis point, the active TWO2 arm was found to be superior to the sham arm, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% CI 1.19, 17.57), P = 0.010. After adjustment for University of Texas Classification (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P = 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P = 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P = 0.013). CONCLUSIONS: This sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.

Extended Perfusion Parameter Estimation from Hyperspectral Imaging Data for Bedside Diagnostic in Medicine.

Background: Hyperspectral Imaging (HSI) has a strong potential to be established as a new contact-free measuring method in medicine. Hyperspectral cameras and data processing have to fulfill requirements concerning practicability and validity to be integrated in clinical routine processes. Methods: Calculating physiological parameters which are of significant clinical value from recorded remission spectra is a complex challenge. We present a data processing method for HSI remission spectra based on a five-layer model of perfused tissue that generates perfusion parameters for every layer and presents them as depth profiles. The modeling of the radiation transport and the solution of the inverse problem are based on familiar approximations, but use partially heuristic methods for efficiency and to fulfill practical clinical requirements. Results: The parameter determination process is consistent, as the measured spectrum is practically completely reproducible by the modeling sequence; in other words, the whole spectral information is transformed into model parameters which are easily accessible for physiological interpretation. The method is flexible enough to be applicable on a wide spectrum of skin and wounds. Examples of advanced procedures utilizing extended perfusion representation in clinical application areas (flap control, burn diagnosis) are presented.

Navigating the landscape of core outcome set development in dermatology.

The development of core outcome sets (COSs; ie, a minimum set of core outcomes that should be measured and reported in all trials or in clinical practice for a specific condition) in dermatology is increasing in pace. A total of 44 dermatology-related COS projects have been registered in the online Core Outcome Measures in Effectiveness Trials database (http://www.comet-initiative.org/studies/search) and include studies on 26 different skin diseases. With the increasing number of COSs in dermatology, care is needed to ensure the delivery of high-quality COSs that meet quality standards when using state-of-the-art methods. In 2015, the Cochrane Skin-Core Outcome Set Initiative (CS-COUSIN) was established. CS-COUSIN is an international, multidisciplinary working group aiming to improve the development and implementation of COSs in dermatology. CS-COUSIN has developed guidance on how to develop high-quality COSs for skin diseases and supports dermatology-specific COS initiatives. Currently, 17 COS development groups are affiliated with CS-COUSIN and following standardized COS development processes. To ensure successful uptake of COSs in dermatology, researchers, clinicians, systematic reviewers, guideline developers, and other stakeholders should use existing COSs in their work.

Deletion of APC7 or APC16 Allows Proliferation of Human Cells without the Spindle Assembly Checkpoint.

The multisubunit ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) is essential for mitosis by promoting timely degradation of cyclin B1. APC/C is tightly regulated by the spindle assembly checkpoint (SAC), which involves MPS1 and MAD2-dependent temporal inhibition of APC/C. We analyzed the contribution of the APC/C subunits APC7 and APC16 to APC/C composition and function in human cells. APC16 is required for APC7 assembly into APC/C, whereas APC16 assembles independently of APC7. APC7 and APC16 knockout cells display no major defects in mitotic progression, cyclin B1 degradation, or SAC response, but APC/C lacking these two subunits shows reduced ubiquitylation activity in vitro. Strikingly, deletion of APC7 or APC16 is sufficient to provide synthetic viability to MAD2 deletion. ΔAPC7ΔMAD2 cells display accelerated mitosis and require SAC-independent MPS1 function for genome stability. These findings reveal that the composition of APC/C critically influences the importance of the SAC in humans.

Hyperspectral imaging as a possible tool for visualization of changes in hemoglobin oxygenation in patients with deficient hemodynamics - proof of concept.

There is a lack of imaging tools for the evaluation of spatial alterations in microcirculation including blood oxygen saturation and hemoglobin distribution but recent innovative developments in hyperspectral technology may offer a solution. We examined different hemodynamic disorders in patients suffering from scleroderma, Dupuytren surgery, chronic foot ulcera and skin infections. Superficial and deeper blood oxygen saturation, hemoglobin distribution and water content were determined using hyperspectral imaging (HSI). In the patient with scleroderma, distinct cutaneous low perfused regions correlated with macroscopic skin aspects and seem to be potential therapy control marker. With HSI accurate clinical evaluation of a macroscopic conspicuous wound after Dupuytren surgery was possible and influenced further surveillance decisions. HSI clearly revealed the spatial geometry and also the clinically related perfusion parameters of abscess formation and chronic ulcer wounds. The hemodynamically relevant parameters like blood oxygen saturation (1 mm to approx. 6 mm subcutaneous), total hemoglobin distribution and tissue water content can be easily determined and visualized with HSI in near real time. Hence, this technique seems to be suitable for routine diagnostics of acute and chronic wounds as well as for the examination of systemic hemodynamic disturbances. Special indications may be transplant surveillance and monitoring of therapeutical interventions.

Thrombogenicity and long-term cytokine removal capability of a novel asymmetric triacetate membrane hemofilter.

Hemofilters applied in continuous renal replacement therapies (CRRTs) for the treatment of acute kidney injury must meet high standards in biocompatibility and permeability for middle and large molecules over extended treatment times. In general, cellulose-based membranes exhibit good biocompatibility and low fouling, and thus appear to be beneficial for CRRT. In this in vitro study, we compared a novel asymmetric cellulose triacetate (ATA) membrane with three synthetic membranes [polysulfone (PS), polyethersulfone (PES), and polyethylenimine-treated acrylonitrile/sodium methallyl sulfonate copolymer (AN69 ST)] regarding thrombogenicity and cytokine removal. For thrombogenicity assessment, we analyzed the thrombin-antithrombin complex (TAT) generation in human whole blood during 5 h recirculation and filtration. Sieving coefficients of interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) were determined using human plasma as test fluid. ATA and AN69 ST membrane permeability were determined also during long-term experiments (48.5 h). ATA exhibited the lowest TAT generation (6.3 µg/L at 5 h), while AN69 ST induced a pronounced concentration increase (152.1 µg/L) and filter clogging during 4 out of 5 experiments. ATA (IL-8: 1.053; IL-6: 1.079; IL-10: 0.898; TNF-α: 0.493) and PES (0.973; 0.846; 0.468; 0.303) had the highest sieving coefficients, while PS (0.697; 0.100; 0.014; 0.012) and AN69 ST (N/A; 0.717; 0; 0.063) exhibited lower permeability. Long-term experiments revealed stronger fouling of the AN69 ST compared to the ATA membrane. We observed the highest permeability for the tested cytokines, the lowest thrombogenicity, and the lowest fouling with the ATA membrane. In CRRT, these factors may lead to increased therapy efficacy and lower incidence of coagulation-associated events.

Hyperspectral imaging: innovative diagnostics to visualize hemodynamic effects of cold plasma in wound therapy.

An important clinical potential of cold atmospheric plasma (CAP) lies in tumor and wound treatment, whereby the last-mentioned is well-referenced already. However, the underlying mechanisms of improved wound healing have not been sufficiently clarified yet, in particular the influence of CAP on microcirculation. Hyperspectral imaging (HSI) enables the visualization of microcirculation of large tissue areas, thus this technique seems to be a candidate to examine CAP effects on perfusion and oxygen saturation in wounds. During clinical wound management, one chronic wound caused by peripheral arterial occlusive disease and one acute wound after surgical removal of cervical lymph nodes were examined using HSI before and after CAP treatment. HSI was able to demonstrate CAP effects on microcirculation showing a relevant increase of superficial and deeper cutaneous oxygen saturation together with elevated hemoglobin concentration in treated and also surrounding wound area. For the first time, it was shown that CAP improves the superficial and deeper oxygenation and hemoglobin perfusion in and around the treated area of acute and chronic wounds. This effect may contribute to healing support by CAP in wounds. HSI seems suitable for evaluating and monitoring CAP effects in clinical settings.