The successful use of polylactide wound dressings for chronic lower leg wounds: A retrospective analysis.

Chronic wounds are a challenging medical entity for patients, medical professionals and healthcare systems. Frequently, patients present themselves to wound specialists after months or even years of unsuccessful treatment. Recent developments have resulted in a multitude of different advanced wound dressings created to treat complex, chronic wounds, one of which is the polylactide dressing Suprathel. This study aimed at investigating the healing potential of Suprathel in chronic wounds and differentiating between old and "young", diabetic and non-diabetic chronic wounds. A prospective, multicentric, non-controlled intervention study was conducted, treating patients with chronic lower leg ulcers (>3 months) with Suprathel and assessing them weekly. Afterwards, a retrospective analysis was performed analysing the wound size initially, after 4 and after 8 weeks of treatment. Furthermore, a differentiation between diabetic and non-diabetic, and chronic wounds older and younger than 12 months, was assessed. A significant reduction in wound size was observed in the study population after 8 weeks of treatment. The effect size in the diabetic wound and the old chronic wound group even reached more than one, with the other groups still showing a large effect of the intervention. This study shows that Suprathel is a valuable tool in the armamentarium of a wound specialist. Not only could we show a positive effect on chronic wounds, we could even demonstrate a significant wound size reduction in chronic wounds of old and young, as well as diabetic wounds, with the treatment of older chronic and diabetic wounds yielding an even larger effect size. Further randomised, controlled studies are necessary to show the full potential of advanced wound dressing materials in large patient cohorts.

Made in Germany: A Quality Indicator Not Only in the Automobile Industry But Also When It Comes to Skin Replacement: How an Automobile Textile Research Institute Developed a New Skin Substitute.

Successful research and development cooperation between a textile research institute, the German Federal Ministry of Education and Research via the Center for Biomaterials and Organ Substitutes, the University of Tübingen, and the Burn Center of Marienhospital, Stuttgart, Germany, led to the development of a fully synthetic resorbable temporary epidermal skin substitute for the treatment of burns, burn-like syndromes, donor areas, and chronic wounds. This article describes the demands of the product and the steps that were taken to meet these requirements. The material choice was based on the degradation and full resorption of polylactides to lactic acid and its salts. The structure and morphology of the physical, biological, and degradation properties were selected to increase the angiogenetic abilities, fibroblasts, and extracellular matrix generation. Water vapor permeability and plasticity were adapted for clinical use. The available scientific literature was screened for the use of this product. A clinical application demonstrated pain relief paired with a reduced workload, fast wound healing with a low infection rate, and good cosmetic results. A better understanding of the product's degradation process explained the reduction in systemic oxidative stress shown in clinical investigations compared to other dressings, positively affecting wound healing time and reducing the total area requiring skin grafts. Today, the product is in clinical use in 37 countries. This article describes its development, the indications for product growth over time, and the scientific foundation of treatments.

Oxygen, pH, Lactate, and Metabolism-How Old Knowledge and New Insights Might Be Combined for New Wound Treatment.

Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metalloproteinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized "bio-reactor," disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and proliferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound's pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wounds. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.

Genome-Wide Association Mapping of Prostrate/Erect Growth Habit in Winter Durum Wheat.

By selecting for prostrate growth habit of the juvenile phase of the cycle, durum wheat cultivars could be developed with improved competitive ability against weeds, and better soil coverage to reduce the soil water lost by evaporation. A panel of 184 durum wheat (Triticum turgidum subsp. durum) genotypes, previously genotyped with DArT-seq markers, was used to perform association mapping analysis of prostrate/erect growth habit trait and to identify candidate genes. Phenotypic data of plant growth habit were recorded during three consecutive growing seasons (2014-2016), two different growth conditions (field trial and greenhouse) and two sowing periods (autumn and spring). Genome-wide association study revealed significant marker-trait associations, twelve of which were specific for a single environment/year, 4 consistent in two environments, and two MTAs for the LSmeans were identified across all environments, on chromosomes 2B and 5A. The co-localization of some MTAs identified in this study with known vernalization and photoperiod genes demonstrated that the sensitivity to vernalization and photoperiod response are actually not only key components of spring/winter growth habit, but they play also an important role in defining the magnitude of the tiller angle during the tillering stage. Many zinc-finger transcription factors, such as C2H2 or CCCH-domain zinc finger proteins, known to be involved in plant growth habit and in leaf angle regulation were found as among the most likely candidate genes. The highest numbers of candidate genes putatively related to the trait were found on chromosomes 3A, 4B, 5A and 6A. Moreover, a bioinformatic approach has been considered to search for functional ortholog genes in wheat by using the sequence of rice and barley tiller angle-related genes. The information generated could be used to improve the understanding of the mechanisms that regulate the prostrate/erect growth habit in wheat and the adaptive potential of durum wheat under resource-limited environmental conditions.

Hybrid durum wheat: heterosis of grain yield and quality traits and genetic architecture of anther extrusion.

KEY MESSAGE: Hybrid durum has a promising yield potential coupled with good quality, but the efficiency of hybrid seed production must be improved. Hybrid breeding is a tremendous success story in many crops, but has not yet made a breakthrough in wheat, mainly due to inefficient hybrid seed production. In this study, we investigated the heterosis for grain yield and important quality traits in durum wheat of 33 hybrids built up from 24 parental lines, as well as the variation in anther extrusion and its genetic architecture in a vast collection of Central European elite durum lines. Average mid-parent heterosis for grain yield was 5.8%, and the best hybrids had a more than one ton per hectare higher grain yield than the best line cultivars. Furthermore, hybrids had a higher grain yield than lines at a given level of protein content or sedimentation value, underpinning their potential for a sustainable agriculture. However, seed set in our experimental hybrid seed production was low. We therefore evaluated 315 elite durum lines for visual anther extrusion, which revealed a large genetic variance and a heritability of 0.66. Results from association mapping suggest a mainly quantitative inheritance of visual anther extrusion with few putative QTL being identified, the largest one explaining less than 20% of the genotypic variance. Genome-wide prediction taking the four largest putative QTL into account yielded a mean cross-validated prediction ability of 0.55. Consequently, breeding for improved male floral characteristics is feasible in durum wheat, but should be mainly based on phenotypic selection.

Copy number variation of Ppd-B1 is the major determinant of heading time in durum wheat.

BACKGROUND: Heading time is an important adaptive trait in durum wheat. In hexaploid wheat, Photoperiod-1 (Ppd) loci are essential regulators of heading time, with Ppd-B1 conferring photoperiod insensitivity through copy number variations (CNV). In tetraploid wheat, the D-genome Ppd-D1 locus is absent and generally, our knowledge on the genetic architecture underlying heading time lacks behind that of bread wheat. RESULTS: In this study, we employed a panel of 328 diverse European durum genotypes that were evaluated for heading time at five environments. Genome-wide association mapping identified six putative QTL, with a major QTL on chromosome 2B explaining 26.2% of the genotypic variance. This QTL was shown to correspond to copy number variation at Ppd-B1, for which two copy number variants appear to be present. The higher copy number confers earlier heading and was more frequent in the heat and drought prone countries of lower latitude. In addition, two other QTL, corresponding to Vrn-B3 (TaFT) and Ppd-A1, were found to explain 9.5 and 5.3% of the genotypic variance, respectively. CONCLUSIONS: Our results revealed the yet unknown role of copy number variation of Ppd-B1 as the major source underlying the variation in heading time in European durum wheat. The observed geographic patterns underline the adaptive value of this polymorphism and suggest that it is already used in durum breeding to tailor cultivars to specific target environments. In a broader context our findings provide further support for a more widespread role of copy number variation in mediating abiotic and biotic stress tolerance in plants.

Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters.

PURPOSE: Since the introduction of ipilimumab (IPI) for the treatment of patients with metastatic malignant melanoma, we have observed remarkable responses after hypofractionated whole brain irradiation (WBRT) or stereotactic radiotherapy (STX) for brain metastases of malignant melanoma. We sought to investigate the impact of the sequence of these treatment modalities. METHODS: We retrospectively evaluated the survival of melanoma patients with brain metastases who were treated with WBRT or STX and received IPI in close temporal relation between October 2010 and March 2015. Follow-up was obtained until November 2016. A total of 27 patients with advanced melanoma and brain metastases who were treated with WBRT before 2010, and who had not received IPI, served as historical controls. RESULTS: We identified a total of 41 patients of whom 15 were treated with STX, 7 with a combination of STX and WBRT and 19 with WBRT alone. All patients received at least 2 doses of IPI. The median time interval between radiotherapy and IPI was 2 months. Patients treated with IPI after radiotherapy had a censored median survival of 11 months, compared with 3 months for the patients who received IPI prior to radiotherapy. Patients who received IPI before radiotherapy showed a similar survival as historical controls, who had not received IPI. We observed long-term survivors after radiotherapy of brain metastases followed by IPI. CONCLUSIONS: These data suggest that the sequence of RT and immune checkpoint inhibition with IPI may be crucial for the success of combined modality treatment of melanoma brain metastases.

Assessing the variation and genetic architecture of asparagine content in wheat: What can plant breeding contribute to a reduction in the acrylamide precursor?

KEY MESSAGE: A large genetic variation, moderately high heritability, and promising prediction ability for genomic selection show that wheat breeding can substantially reduce the acrylamide forming potential in bread wheat by a reduction in its precursor asparagine. Acrylamide is a potentially carcinogenic substance that is formed in baked products of wheat via the Maillard reaction from carbonyl sources and asparagine. In bread, the acrylamide content increases almost linearly with the asparagine content of the wheat grains. Our objective was, therefore, to investigate the potential of wheat breeding to contribute to a reduction in acrylamide by decreasing the asparagine content in wheat grains. To this end, we evaluated 149 wheat varieties from Central Europe at three locations for asparagine content, as well as for sulfur content, and five important quality traits regularly assessed in bread wheat breeding. The mean asparagine content ranged from 143.25 to 392.75 mg/kg for the different wheat varieties, thus underlining the possibility to reduce the acrylamide content of baked wheat products considerably by selecting appropriate varieties. Furthermore, a moderately high heritability of 0.65 and no negative correlations with quality traits like protein content, sedimentation volume and falling number show that breeding of quality wheat with low asparagine content is feasible. Genome-wide association mapping identified few QTL for asparagine content, the largest explaining 18% of the genotypic variance. Combining these QTL with a genome-wide prediction approach yielded a mean cross-validated prediction ability of 0.62. As we observed a high genotype-by-environment interaction for asparagine content, we recommend the costly and slow laboratory analysis only for late breeding generations, while selection in early generations could be based on marker-assisted or genomic selection.

Periodontal damage after thermal inhalation injury - The impact of high temperature inhalation injury on long term periodontal health.

PURPOSE: Thermal inhalation injury is a common, life-threatening problem in burned patients. Whether or not this single event of damage to the oral integrity causes long term health problems is yet to be examined. MATERIAL AND METHODS: All consecutive burn patients between 2014 and 2017 of Marienhospital Stuttgart (MHS), Germany, with at least 10% of burned skin surface were included and compared. The Periodontal Screening Index as well as Vitamin D levels were examined. Vitamin D has been suspected to contribute to the genesis of periodontitis. Risk factors and subjective oral life quality were prompted. RESULTS: We included a total of 32 patients, 15 of which had an inhalation injury in their medical history. Risk factors were examined via Renatus' questionnaire. While risk factors were equally distributed in both groups we saw a remarkable difference in periodontal integrity, with the Periodontal Screening Index (PSI) per sextant differing drastically (with inhalation injury: 2.40, without inhalation injury: 1.10, p < 0.001). Patients with an inhalation injury had a mean of 5.2 out of 6 possible sextants with a pathologic PSI (with the median being 6/6), while patients without an inhalation injury had a mean of 1.83 out of 6 (median: 1/6), p < 0.001. The oral health impact profile showed a difference as well, albeit without statistical significance (with inhalation injury: median = 11, without: median = 3.5, p = 0.414). A correlation between Serum Vitamin D levels and periodontal integrity could not be seen in this group. CONCLUSION: Inhalation injury is a possible cause for periodontitis and hence impacts the quality of life of burned patients.

[Impact of the COVID-19 crisis in Spring 2020 on trauma case numbers of an academic teaching hospital in Stuttgart : Trauma during a pandemic]. / Einfluss der COVID-19-Krise im Frühjahr 2020 auf traumatologische Fallzahlen eines akademischen Lehrkrankenhauses in Stuttgart : Trauma während einer Pandemie.

BACKGROUND: To cope with the COVID-19 outbreak in Germany, the government imposed a lockdown, which led to restrictions and lifestyle changes for the population. PURPOSE: This study aimed to evaluate the impact of the lockdown on activities causing trauma and the consultation in emergency rooms. MATERIAL AND METHODS: All consecutive trauma patients consulting the Emergency Department of the Marienhospital Stuttgart (MHS), Germany, during the 6 weeks preceding the lockdown, during and after the lockdown were included. The time and type of consultation, treatment received, Manchester triage score, type of trauma, the anatomical region of the injury as well as demographic data were reported and compared. RESULTS: The study included 551 cases during lockdown, 943 cases before and 783 cases after the lockdown. We observed a reduced caseload during the lockdown of 41.6% compared to before and of 29.7% compared to after (p < 0.001). Patients were on average older in the observation group than in both control groups (before : 51.5 years, lockdown: 56.1 years, after: 51.6 years) (p < 0.001). Injuries to the head and neck were constant (25.0%, 25.4%, 25.5%). We noticed lower limb injuries decreasing (26.1%, 22.3%, 22.7%) and upper limb injuries increasing (25.5%, 31.8%, 30.1%). A decrease in sports injuries (11.1%, 5.1%, 9.1%) and work accidents (16.1%, 10.7%, 12.8%) resulted in more domestic accidents (30.4%, 52.5%, 31.8%). Self-referral decreased (67.7%, 53.2%, 60.3%) while referral via paramedics increased (28.3%, 38.7%, 35.6). Blunt trauma was the most common cause of injury (55.6%, 61.0%, 55.3%). Indications for surgery were higher (16.8%, 21.6%, 14.0%). CONCLUSION: The lockdown and restrictions in personal life and daily routine had an impact on the frequency, etiology and management of trauma patients in Stuttgart.

Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study.

Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of CTL from the tumor were correlated with significant prognostic detriment. Hypoxic tumors overall have smaller amounts of CTL, and spatial analysis revealed a repellent effect of hypoxia on CTL. In contrast to in vitro studies, specific upregulation of ADO-related enzymes CD73 and CD39 in GLUT-1high tumor regions was never observed. In this study, we could show direct in vivo evidence for hypoxia-mediated immunosuppression in melanoma. Moreover, this study suggests a significant prognostic relevance of the tumor immune phenotype, the strength of CD8 infiltration in the tumor, and the expression of hypoxia marker GLUT-1 on melanoma cells. Last, our results suggest a temporal stability of the microenvironment-mediated immunosuppressive phenotype in melanoma.

Aroma and quality of breads baked from old and modern wheat varieties and their prediction from genomic and flour-based metabolite profiles.

Bread aroma is the principal characteristic perceived by the consumer yet it is mostly disregarded in the product chain. The main aim of this study was to evaluate the potential to include bread aroma as a new target criterion into the wheat product chain. The objectives of our study were to (i) quantify the influence of genetic versus environmental factors on the bread aroma and quality characteristics, (ii) evaluate whether bread baked from modern wheat varieties differ in terms of aroma from those baked from old varieties, and (iii) compare genomic and metabolomic approaches for their efficiency to predict bread aroma and quality characteristics in a wheat breeding program. Agronomic characters as well as bread aroma and quality traits were assessed for 18 old and 22 modern winter wheat varieties evaluated at up to three locations in Germany. Metabolite profiles of all 120 flour samples were collected using a 7200 GC-QTOF. Considerable differences in the adjusted entry means for all examined bread aroma and quality characters were observed. For aroma, which was rated on a scale from 1 to 9, the adjusted entry means varied for the 40 wheat varieties between 3 and 8. In contrast, the aroma of bread prepared from old and modern wheat varieties did not differ significantly (P < 0.05). Bread aroma was not significantly (P < 0.05) correlated with grain yield, which suggested that it is possible to select for the former character in wheat breeding programs without reducing the gain of selection for the latter. Finally, we have shown that bread aroma can be better predicted using a combination of metabolite and SNP genotyping profiles instead of the SNP genotyping profile only. In conclusion, we have illustrated possibilities to increase the quality of wheat for consumers in the product chain.