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Abstract Background End-to-end and end-to-side anastomoses remain the most common techniques in microsurgical free flap reconstruction. Still, there is an ongoing effort to optimize established techniques and develop novel techniques. Numerous comparative studies have investigated flow dynamics and patency rates of microvascular anastomoses and their impact on flap survival. In contrast, few studies have investigated whether the type of anastomosis influences the outcome of microvascular free flap reconstruction of a lower extremity. Patients and Methods Retrospectively, we investigated the outcome of 131 consecutive free flaps for lower extremity reconstruction related to the anastomotic technique. Results No statistical significance between arterial or venous anastomoses were found regarding the anastomotic techniques (p = 0.5470). However, evaluated separately by vessel type, a trend toward statistical significance for anastomotic technique was observed in the arterial (p = 0.0690) and venous (p = 0.1700) vessels. No thromboses were found in arterial end-to-end anastomoses and venous end-to-side anastomoses. More venous (n = 18) than arterial thromboses (n = 9) occurred in primary anastomoses undergoing microsurgical free flap reconstruction (p = 0.0098). Flap survival rate was 97.37% in the end-to-end arterial group versus 86.36% in the end-to-side group. No thromboses were found in five arterial anastomoses using T-patch technique. Conclusion For lower extremities, there is a connate higher risk for venous thrombosis in anastomotic regions compared with arterial thrombosis. We observed divergent rates for thromboses between end-to-end and end-to-side anastomoses. However, if thrombotic events are explained by anastomotic technique and vessel type, the latter carries more importance. more...

Abstract Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2 −/− CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies. more...

Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection. more...

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors. more...

While much study has been dedicated to investigating biopolymers' stress-strain response at low strain levels, little research has been done to investigate the almost linear region of biopolymers' stress-strain response and how the microstructure affects it. We propose a mathematical model of fibrous networks, which reproduces qualitative features of collagen gel's stress-strain response and provides insight into the key features which impact the Young's modulus of similar fibrous tissues. This model analyzes the relationship of the Young's modulus of the lattice to internodal fiber length, number of connection points or nodes per unit area, and average number of connections to each node. Our results show that fiber length, nodal density, and level of connectivity each uniquely impact the Young's modulus of the lattice. Furthermore, our model indicates that the Young's modulus of a lattice can be estimated using the effective resistance of the network, a graph theory technique that measures distances across a network. Our model thus provides insight into how the organization of fibers in a biopolymer impact its Young's modulus., (Copyright © 2022 by ASME.) more...

In this study, we present the experimental results for stable barium (Ba) isotope fractionation ( 137 Ba/ 134 Ba) during the transformation of aragonite (CaCO 3 ) and gypsum (CaSO 4 ·2H 2 O) in Ba-bearing aqueous solution to witherite (BaCO 3 ) and barite (BaSO 4 ), respectively. The process was studied at three temperatures between 4 and 60 °C. In all cases, the transformation leads to a relative enrichment of the lighter 134 Ba isotope in the solid compared to the aqueous solution, with 137/134 Ba enrichment factors between -0.11 and -0.17 ‰ for BaCO 3 , and -0.21 and -0.26 ‰ for BaSO 4 . The corresponding mass-dependent 138/134 Ba enrichment factors are -0.15 to -0.23 ‰ for BaCO 3 , and -0.28 to -0.35 ‰ for BaSO 4 . The magnitude of isotope fractionation is within the range of recent reports for witherite and barite formation, as well as trace Ba incorporation into orthorhombic aragonite, and no substantial impact of temperature can be found between 4 and 80 °C. In previous studies, ion (de)solvation has been suggested to impact both the crystallization process of Ba-bearing solids and associated Ba isotope fractionation. Precipitation experiments of BaSO 4 and BaCO 3 using an methanol-containing aqueous solution indicate only a minor effect of ion and crystal surface (de)solvation on the overall Ba isotope fractionation process. more...

Background The ideal starting point for flap training (FT) with the combined wrapping and dangling procedure is still a question of debate. Most units follow their own established protocols and currently evidence of flap compromise due to FT is still lacking. The aim of this study was to prove if an early and "aggressive" wrapping and dangling protocol could lead to metabolic changes, measured by microdialysis, indicating ischemia resulting in compromised flap perfusion. Methods Between 2010 and 2014, 49 patients with microvascular free flap reconstruction of the lower limb were included in this study. Patients were randomized into two groups. Group I started FT on the 7th postoperative day, and group II started on day 3. FT consisted of a combined wrapping and dangling procedure doubling its duration daily and ending at day 5. Flaps were monitored clinically and by microdialysis for ischemia-induced changes and metabolic parameters in the flap tissue in respect to different starting points of FT. Results All 49 patients in both groups were able to complete the postoperative FT without complications. Noninferiority of the early group could be proven and microdialysis results showed no differences between both groups. Conclusion We could prove by microdialysis that an early start of FT does not lead to compromised flap perfusion. Moreover, an early start of FT can lead to a reduced length of hospital stay. Furthermore, a reduced risk for deep vein thrombosis, pulmonary embolism, and pneumonia due to earlier mobilization might be an appreciated side effect., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.) more...

The prevalent formation of noncrystalline U(IV) species in the subsurface and their enhanced susceptibility to reoxidation and remobilization, as compared to crystalline uraninite, raise concerns about the long-term sustainability of the bioremediation of U-contaminated sites. The main goal of this study was to resolve the remaining uncertainty concerning the formation mechanism of noncrystalline U(IV) in the environment. Controlled laboratory biofilm systems (biotic, abiotic, and mixed biotic-abiotic) were probed using a combination of U isotope fractionation and X-ray absorption spectroscopy (XAS). Regardless of the mechanism of U reduction, the presence of a biofilm resulted in the formation of noncrystalline U(IV). Our results also show that biotic U reduction is the most effective way to immobilize and reduce U. However, the mixed biotic-abiotic system resembled more closely an abiotic system: (i) the U(IV) solid phase lacked a typically biotic isotope signature and (ii) elemental sulfur was detected, which indicates the oxidation of sulfide coupled to U(VI) reduction. The predominance of abiotic U reduction in our systems is due to the lack of available aqueous U(VI) species for direct enzymatic reduction. In contrast, in cases where bicarbonate is present at a higher concentration, aqueous U(VI) species dominate, allowing biotic U reduction to outcompete the abiotic processes. more...

Knowledge of paleo-redox conditions in the Earth's history provides a window into events that shaped the evolution of life on our planet. The role of microbial activity in paleo-redox processes remains unexplored due to the inability to discriminate biotic from abiotic redox transformations in the rock record. The ability to deconvolute these two processes would provide a means to identify environmental niches in which microbial activity was prevalent at a specific time in paleo-history and to correlate specific biogeochemical events with the corresponding microbial metabolism. Here, we demonstrate that the isotopic signature associated with microbial reduction of hexavalent uranium (U), i.e., the accumulation of the heavy isotope in the U(IV) phase, is readily distinguishable from that generated by abiotic uranium reduction in laboratory experiments. Thus, isotope signatures preserved in the geologic record through the reductive precipitation of uranium may provide the sought-after tool to probe for biotic processes. Because uranium is a common element in the Earth's crust and a wide variety of metabolic groups of microorganisms catalyze the biological reduction of U(VI), this tool is applicable to a multiplicity of geological epochs and terrestrial environments. The findings of this study indicate that biological activity contributed to the formation of many authigenic U deposits, including sandstone U deposits of various ages, as well as modern, Cretaceous, and Archean black shales. Additionally, engineered bioremediation activities also exhibit a biotic signature, suggesting that, although multiple pathways may be involved in the reduction, direct enzymatic reduction contributes substantially to the immobilization of uranium. more...

Unlabelled: Flap loss due to postoperative flap edema and thrombosis of the anastomosis remains the predominant concern of reconstructive microsurgeons. Due to the lack of scientific evidence, there is no unanimous opinion on when to mobilize a reconstructed lower extremity, reflecting the uncertainty of plastic surgeons regarding the effect of the dangling procedure on flap microcirculation., Patients and Methods: In this randomized controlled clinical trial, we included 31 patients undergoing free flap transfer to the lower extremity.The patients were randomly divided into two groups. Cohort I consisted of 15 patients starting the dangling procedure at day 7, and cohort II consisted of 16 patients in which an early aggressive postoperative dependency started at day 3.Wrapping and dangling of the flap was performed primarily with a duration of 5 minutes three times a day and increased daily by doubling the duration over a period of 4 days, reaching 60 minutes at day 5.Before and immediately after each dangling procedure the flaps were clinically monitored under direct observation for color, capillary refill, venous congestion, flap turgor, and flap temperature., Results: In all cases the postoperative course was uneventful, resulting in a success rate of 100%. No adverse effects or flap compromise were seen due to the combined dangling/wrapping procedure., Conclusion: An early and aggressive start of a combined dangling/wrapping procedure does not compromise flap circulation and allows mobilizing patients after free flap transfer to the lower extremity at an early stage. This approach improves patient comfort, shortens the hospital stay, and therefore reduces socioeconomic costs., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.) more...

In this study, we present the first experimental results for stable barium (Ba) isotope ((137)Ba/(134)Ba) fractionation during low-temperature formation of the anhydrous double carbonate BaMn[CO(3)](2). This investigation is part of an ongoing work on Ba fractionation in the natural barium cycle. Precipitation at a temperature of 21±1°C leads to an enrichment of the lighter Ba isotope described by an enrichment factor of-0.11±0.06‰ in the double carbonate than in an aqueous barium-manganese(II) chloride/sodium bicarbonate solution, which is within the range of previous reports for synthetic pure BaCO (3) (witherite) formation. more...

The importance of ergonomic workplace design has been rising incredibly. The knowledge of the interaction with a view to many indicators (e.g. operators' health, quality, productivity etc.) in the automotive assembly shop pushed into another thinking of ergonomics and an increasing awareness of economic possibilities relating to benefits and cost savings aligned with ergonomics. The paper discusses exemplary the various indicators and factors which could be influenced by ergonomic workplace design. These factors are linked each other and support the statement of ergonomic efficiency. Thus, the aim of this paper is to present a model which describes that investments in ergonomic work placement acts with preventive measurements, minimization of losses (refinishing operations, compensation money etc.) and extensive economies on the whole company. more...