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Introduction: Free tissue transfer has added to the plastic surgeon's armamentarium and has afforded patients more chances towards limb salvage in recent decades following severe trauma. Venous congestion is a common occurrence, can be the result of several reasons and has devastating results in patients' outcomes. Recent studies have highlighted the importance of restrictive fluid administration. We hypothesized that a restrictive fluid administration in the intra – operative period would be associated with a lower incidence of venous congestion in patients undergoing free flap reconstruction of traumatic defects of the extremities. Methods: All patients undergoing a perforator free flap soft tissue reconstruction of traumatic defects of the extremities, from 2005 to 2019 were retrospectively identified. Patient's demographics, comorbidities and technical aspects of the operation were extracted. The study population was divided in two groups based on the amount of fluids administered (restrictive: < 6 ml/kg/hr; liberal: ≥ 6 ml/kg/hr). Multivariate analyses were performed to identify the impact of fluid strategy on the development of clinically significant venous congestion. Results: A total of 75 patients were identified. Out of these, 24 patients had clinically significant venous congestion. Fluid administration strategy [AOR (95% CI): 1.53 (1.22, 1.92)], use of the superficial venous system [0.03 (0.01, 0.26)], operative time [1.98 (1.97, 1.99)] and age>50 [5.60 (1.10, 28.52)]. A cut – off analysis identified 6 ml/kg/hr as the cut off point for fluid administration. Liberal fluid administration (≥6 ml/kg/hr) was independently associated with a higher incidence of venous congestion and return to the OR for flap debridement, both overall and after exclusion of anastomotic revisions. Conclusions: Venous congestion in free flap reconstruction following traumatic defects of the extremities remains high. Several factors are associated with congestion. Liberal fluid administration ≥6 ml/kg/hr is independently associated with this complications and should be avoided when possible.

Carpal tunnel is the most common peripheral compressive neuropathy. Nonoperative management may provide temporary alleviation of symptoms, but in most cases surgical decompression is warranted. There are a multitude of approaches ranging from open release under general anesthesia to wide awake in-office endoscopic carpal tunnel release. The present article describes the technical considerations for the single incision, antegrade approach to endoscopic carpal tunnel release using the SEGWay system and technique.

Expression of miRNAs is critical for the regulation of several cell functions including proliferation, migration, differentiation, and survival, as well as extracellular matrix (ECM) remodeling. The dynamic interplay between miRNAs, ECM macromolecules, and the tumor microenvironment plays critical roles in many aspects of human diseases such as metabolic disorders and cancers. Circulating and secreted miRNAs, via membrane vesicles, affect cell-cell communication and cellular metabolic pathways, underscoring their significance in tumor progression. The primary goal of this article is to highlight the importance of epigenetic regulatory factors, focusing on miRNA-mediated ECM reorganization and their functional relationships, and how matrix-mediated miRNAs affect tumor progression.

Rationale. There is a paucity of prospective UK studies exploring the role of Adverse Childhood Experiences (ACEs) on adolescent teenage drug use and even less is known about the complex interplay between ACEs and adolescent social, demographic, and economic characteristics. To address these gaps, we use rich longitudinal data from the nationally representative Millennium Cohort Study. Methods. Sex-stratified survey logistic regression modelling was applied using data from 9,476 adolescents and their parents to examine associations between ACEs between ages 3 and 14 years and drug use at ages 14 and 17 years. We a) explore the extent to which associations are robust to adjustment for ethnicity, family income, parental social class, and parental education, b) examine whether associations differ by these factors, and c) estimate the proportion of drug use at ages 14 and 17 years attributable to ACEs after controlling for these factors. Results. Half of MCS cohort members had been exposed to at least one ACE and approximately 1 in 11 were exposed to 3+ ACEs. Multivariable analyses suggest that ACEs were associated with a higher likelihood of drug use at age 14 than age 17, especially for girls. No evidence was found that either advantaged socio-economic position or ethnicity acted as a buffer against the negative effects of ACEs in relation to adolescent drug use. Finally, we found that prevention of exposure to sexual violence, bullying and violence within the household (if causal) is more important for girls’ drug use at age 14 than age 17. Conclusions. ACEs are associated with adolescent drug use with potential consequences on wider aspects of young people's lives, regardless of their social, ethnic, or economic background, adding further urgency to the need to reduce the incidence of these negative experiences.

Amyloid deposition of WT human β2-microglobulin (WT-hβ2m) in the joints of long-term hemodialysis patients is the hallmark of dialysis-related amyloidosis. In vitro, WT-hβ2m does not form amyloid fibrils at physiological pH and temperature unless co-solvents or other reagents are added. Therefore, understanding how fibril formation is initiated and maintained in the joint space is important for elucidating WT-hβ2m aggregation and dialysis-related amyloidosis onset. Here, we investigated the roles of collagen I and the commonly administered anticoagulant, low-molecular-weight (LMW) heparin, in the initiation and subsequent aggregation phases of WT-hβ2m in physiologically relevant conditions. Using thioflavin T fluorescence to study the kinetics of amyloid formation, we analyzed how these two agents affect specific stages of WT-hβ2m assembly. Our results revealed that LMW-heparin strongly promotes WT-hβ2m fibrillogenesis during all stages of aggregation. However, collagen I affected WT-hβ2m amyloid formation in contrasting ways: decreasing the lag time of fibril formation in the presence of LMW-heparin and slowing the rate at higher concentrations. We found that in self-seeded reactions, interaction of collagen I with WT-hβ2m amyloid fibrils attenuates surface-mediated growth of WT-hβ2m fibrils, demonstrating a key role of secondary nucleation in WT-hβ2m amyloid formation. Interestingly, collagen I fibrils did not suppress surface-mediated assembly of WT-hβ2m monomers when cross-seeded with fibrils formed from the N-terminally truncated variant ΔN6-hβ2m. Together, these results provide detailed insights into how collagen I and LMW-heparin impact different stages in the aggregation of WT-hβ2m into amyloid, which lead to dramatic effects on the time course of assembly.

Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms.

The overall structure and architecture of the extracellular matrix undergo dramatic alterations in composition, form, and functionality over time. The stochasticity begins during development, essential for maintaining organismal homeostasis and is heavily implicated in many pathobiological states including fibrosis and cancer. Modeling and remodeling of the matrix is driven by the local cellular milieu and secreted and cell-associated components in a framework of dynamic reciprocity. This collection of expertly-written reviews aims to relay state-of-the-art information concerning the mechanisms of matrix modeling and remodeling in physiological development and disease.

Background: Obstructive jaundice caused by abdominal aortic aneurysm (AAA) is an extremely rare clinical presentation. We present an 85-year-old male with a large intact AAA causing obstructive jaundice and review the relevant literature. Methods and Results: The patient was referred to our hospital with jaundice and a palpable pulsatile abdominal mass. Computerized tomography (CT) angiogram and magnetic resonance cholangiopancreatography (MRCP) revealed an infrarenal AAA with maximal diameter of 8.5 cm compressing the pancreatic head and common bile duct, causing obstructive jaundice with elevated levels of total and direct bilirubin. The patient was subjected to endovascular aneurysm repair (EVAR). Blood bilirubin gradually decreased to normal levels. No complications were reported during the immediate postoperative and at 3-month follow up period. Literature review suggests that our case is one of the largest intact AAAs which have been reported to cause biliary obstruction. Conclusions: AAAs causing secondary obstructive jaundice is an uncommon clinical presentation requiring high clinical suspicion during differential diagnosis, so that patients can receive proper and early diagnosis and treatment.

Motivated by reeling installation of mechanically-lined offshore steel pipes, the present paper investigates the structural performance of a bi-material lined pipe under cyclic bending, using advanced finite element tools. A three-dimensional finite element model is developed, simulating the manufacturing process of the lined pipe in the first stage of the analysis, followed by the cyclic bending response of the lined pipe in the second stage. Five bending cycles are considered, representing the two installation cycles and three additional cycles of a failure-repair scenario. The loading cycles impose a bending curvature range corresponding to the strains developed during a typical reeling installation process. Different loading patterns are considered and their effect on liner performance are investigated. The results show that the application of reverse (negative) curvature during the loading cycles, representing the straightener, has a significant influence on the wrinkle size of the liner developed at the two critical generators, and its rate of increase, compared with cyclic bending patterns with non-negative curvature. Numerical results on imperfection sensitivity are obtained, considering two types of imperfection of the liner pipe. In addition, the structural performance of liners with different thickness is examined, and the results show that there exists a minimum value of wall thickness, above which the liner does not exhibit local buckling at the end of the cyclic loading history. The beneficial effect of internal pressure on liner cyclic response is also verified, especially for thin-walled liners, preventing the development of wrinkles. Finally, the effect of manufacturing process is examined, showing the superior structural performance of partially-heated lined pipes, with respect to fully-heated lined pipes, and to lined pipes manufactured by purely-mechanical process.

This study performs a combined 0-dimensional/3-dimensional modelling ap-proach to investigate the fluid flow and heat transfer characteristics of a busthermal management systems. The 3-dimensional model is deployed to de-velop new correlations for the heat transfer coefficient (Colburn-j factor) andthe friction factor (Fanning-f factor) at the air-side of the multi-louver ra-diator and charge-air cooler. The effect of the fan operation is also takeninto account. The existing correlations in the literature developed for carswhere the radiator and charge-air cooler are placed in the front section ofthe vehicle exposed to a uniform incoming air flow. While in buses, thesecomponents are placed at the vehicle rear section and in contact with a turbu-lent and non-uniform air flow, highlighting the need for development of newColburn-j factor and the Fanning-f factor for air flow within the louvered finsin these two components The coefficients developed are incorporated into the0-dimensional model to predict the thermal characteristics of the bus under-hood for a range of operating conditions. The 0-dimensional model simulatesthe heat interaction of the multiple thermodynamic systems. Thus, a betterunderstanding of the thermal management is achieved by investigating the energy distribution within the engine compartment and describing the per-formance of the thermal systems. The 0-dimensional/3-dimensional model isexamined under the peak brake power condition. A coolant mass flow rate of3.74 kg/s and fans speed of 4000rpm are the most optimum results since thecoolant’s temperature is decreased by 5◦C and the parasitic losses are keptat minimum.

Risk factors for chronic venous disease (CVD) have been widely reported in population health management. However, predisposing factors associated with patients treated for advanced stages of CVD have yet to be established. We examined the demographics and risk factors associated with advanced clinical presentation of CVD for patients referred for vein ablation.Retrospective analysis of our institutional Vascular Quality Initiative Varicose Vein Registry included endovenous laser treatment and radiofrequency ablation procedures at our tertiary institution, community hospital, and outpatient vein clinic between January 2015 and December 2016. All incompetent truncal veins were divided into two groups based on the Clinical, Etiology, Anatomy, and Pathophysiology clinical class of CVD: mild-moderate (C1-C3) and severe (C4-C6). The two groups were compared in terms of their demographics and medical comorbidities using univariate and multivariate analysis. Data analysis was conducted on SPSS 22.0 (IBM Corp, Armonk, NY).During the study period, a total of 650 incompetent truncal veins were ablated. The mean age of patients was 58 years, and 73% were female. Severe CVD composed 21% of the cohort. Male sex was a risk for advanced CVD (odds ratio, 2.6; P .001). Older age was also associated with severe CVD; the average age was 63 years for patients with advanced stage CVD vs 56 years for mild to moderate CVD (P .001). Race, diabetes, body mass index, number of pregnancies, congestive heart failure, history of venous thromboembolism, current anticoagulation, and history of smoking or current smoking status did not affect the severity of CVD.Among patients treated with vein ablation for superficial venous insufficiency, older age and male sex were associated with increased severity of advanced CVD. Despite the higher incidence of varicose veins among women, men are more likely to have clinically advanced CVD when they present for truncal vein ablation.

Breast cancer is the most common malignancy among women worldwide. The role of epidermal growth factor receptor (EGFR) in many epithelial malignancies has been established, since it is dysregulated, overexpressed or mutated. Its overexpression has been associated with increased aggressiveness and metastatic potential in breast cancer. The well-established interplay between EGFR signaling pathway and estrogen receptors (ERs) as well as major extracellular matrix (ECM) mediators is crucial for regulating basic functional properties of breast cancer cells, including migration, proliferation, adhesion and invasion. EGFR activation leads to endocytosis of the receptor with implications in the regulation of downstream signaling effectors, the modulation of autophagy and cell survival. Therefore, EGFR is considered as a promising therapeutic target in breast cancer. Several anti-EGFR therapies (i.e. monoclonal antibodies and tyrosine kinase inhibitors) have been evaluated both in vitro and in vivo, making their way to clinical trials. However, the response rates of anti-EGFR therapies in the clinical trials is low mainly due to chemoresistance. Novel drug design, phytochemicals and microRNAs (miRNAs) are assessed as new therapeutic approaches against EGFR. The main goal of this review is to highlight the importance of targeting EGFR signaling pathway in terms of its crosstalk with ERs, the involvement of ECM effectors and epigenetics. Moreover, recent insights into the design of specialized delivery systems contributing in the development of novel diagnostic and therapeutic approaches in breast cancer are addressed.

The mechanical behavior of spiral-welded large-diameter steel pipes is simulated, with the purpose of defining their bending deformation capacity against local buckling. The steel pipes are candidates for hydrocarbon onshore pipeline applications with diameter-to-thickness ratio D/t equal to 53 and 69, and are subjected to longitudinal bending under internal pressure levels ranging from zero to 75% of the nominal yield pressure. Initial geometric imperfections are considered in the form of short-wave axial wrinkles and girth weld misalignment, whereas residual stresses are taken into account as computed from a special-purpose finite element simulation of the spiral bending process, which also accounts for both de-coiling process and hydrotesting. The sensitivity of critical bending curvature on the level of internal pressure is examined, the value of buckling wave length is discussed and the effects of hydrotesting after spiral forming on structural performance are also investigated. Finally, the value of critical bending curvature is compared with analytical and empirical equations, widely used in pipeline design applications. The results of the present study determine the main parameters affecting the buckling deformation capacity of large-diameter spiral welded pipes in a strain-based design framework, and indicate that these pipes can be used in demanding pipeline applications, such as in geohazard areas.

Ground-supported unanchored liquid-storage cylindrical tanks, when subjected to strong seismic loading may exhibit uplifting of their bottom plate, which may have significant effects on their dynamic behavior and structural integrity. In particular, due to uplifting, a substantial amount of plastic deformation develops at the vicinity of the welded connection between the tank shell and the bottom plate that may cause failure of the welded connection due to fracture or fatigue, associated with loss of tank containment. The present study focuses on the base uplifting mechanism and tank performance with respect to the shell/plate welded connection through a numerical simple and efficient methodology that employs primarily a simplified modeling of the tank as a spring-mass system for dynamic analysis, enhanced by a nonlinear spring at its base to account for the effects of uplifting, supported by a detailed finite element model of the tank for incremental static analysis. The latter model is capable of describing with accuracy the state of stress and deformation at different levels of lateral loading, in order to obtain the overturning moment-rocking angle relationship to be used in the simplified model. The methodology is applied in two cylindrical liquid storage tanks of different aspect ratios focusing on local performance of the welded connection, towards assessing the strength of the welded connection. The numerical results provide better understanding of tank uplifting mechanics and strength against failure of the welded connection at the tank bottom. Furthermore, the proposed methodology can be used for efficient assessment of uplifting effects on tank structural safety, towards minimizing seismic risk in industrial facilities.

Progressive loss of organ function in most organs is associated with fibrosis, a tissue state associated with abnormal matrix buildup. If highly progressive, the fibrotic process eventually leads to organ failure and death. Fibrosis is a basic connective tissue lesion defined by the increase in the amount of fibrillar extracellular matrix (ECM) components in a tissue or organ. In addition, intrinsic changes in important structural cells can induce the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. ECM enzymes belonging to the family of matrix metalloproteinases (MMPs) and lysyl oxidases (LOXs) play a crucial role in ECM remodeling and regeneration. MMPs have a catalytic role in degradation of ECM, whereas LOX/LOXLs mediate ECM, especially collagen, cross-linking and stiffening. Importantly, enzymes from both families are elevated during the fibrotic response to tissue injury and its resolution. Yet, the apparent molecular competition or antagonistic activities of these enzyme families during the various stages of fibrosis is often overlooked. In this review, we discuss the diverse roles of MMPs and LOX/LOXL2 in chronic organ fibrosis. Finally, we review contemporary therapeutic strategies for fibrosis treatment, based on neutralization of MMP and LOX activity, as well as the development of novel drug delivery approaches.

In geohazard areas, buried pipelines are subjected to permanent ground-induced deformations, which constitute major threats for their structural safety. Geohazards include seismic fault movement, liquefaction-induced lateral spreading, slope instability or soil subsidence, and are associated with the development of severe strains in the pipeline. Calculation of these strains is necessary for assessing pipeline integrity. In the present paper, an analytical methodology is presented that allows for simple and efficient pipeline strain analysis in geohazard areas. The methodology is compared with existing more elaborate analytical methodologies and finite element predictions. The analytical formulation results in closed form expressions and the model contributes to better understanding of buried pipeline behavior subjected to permanent ground-induced deformations. The proposed methodology is directly applicable to fault actions, but it can be also applicable to a wide range of geohazards. Furthermore, using this methodology, one may predict the strains developed in the pipeline wall due to ground-induced actions in a simple and efficiently manner and is suitable for the preliminary design of pipelines.

A three-dimensional numerical model of a mechanically bonded lined pipe is developed, simulating its structural response during the reeling installation method. An installation/failure–repair scenario is considered with five winding–unwinding cycles, accounting for the straightening process. The cyclic deformation of a lined pipe is presented, monitoring ovalization, local curvature and liner detachment from the outer pipe during reeling. The influence of pipe contact with the reel, and the effects of back tension on the structural response of the lined pipe are examined. The results indicate a residual curvature of the pipeline at the end of unspooling. Applying different levels of back tension, the local curvature on the pipe decreases, affecting the detachment of the liner pipe from the outer pipe. Numerical results on imperfection sensitivity demonstrate the significant influence of geometric imperfections on liner buckling. Comparison of the present results with those from a pure bending model shows that a lower liner detachment rate is predicted by the present model. Furthermore, the reeling performance of thicker liners is examined, showing the gradual reduction of liner detachment with increasing wall thickness. Finally, the reeling process in the presence of moderate levels of internal pressure is simulated, verifying its beneficial effect on structural performance, preventing local buckling.