Dorsal Plating, Lateral Plating, and Intramedullary Screw Fixation of Extra-Articular Proximal Phalangeal Fractures: A Cadaveric Biomechanical Comparison.

PURPOSE: To provide a biomechanical comparison of dorsal plating, lateral plating and intramedullary screw [IMS] fixation for extra-articular proximal phalangeal fractures. METHODS: Midshaft osteotomies were performed on 36 cadaveric proximal phalanges. The phalanges were fixed by dorsal plating, lateral plating or IMS fixation, and subjected to a four-point bending force. Force was applied to achieve displacement of 1 mm/s, until construct failure or to a maximum of 10 mm of displacement. Clinical failure was defined as 2 mm of displacement, and force required to result in 1 mm and 2 mm of displacement was recorded, as was mode of failure. RESULTS: Dorsal plating [127.5 N ± 52.6; 46.51-229.17] and lateral plating [77.1 N ± 25.1; 48.3-113.8] required significantly greater force to achieve 1 mm of displacement when compared to IMS [41.2 N ± 12.4; 20.6-62.3]. Dorsal plating [339.2 N ± 91.8; 158.5-538.6] required significantly greater force than lateral plating [154.5 N ± 33.8; 99.0 -204.4] and intramedullary screw fixation [110.0 ± 38.6; 51.1-189.3] to result in 2 mm of displacement. Lateral and dorsal plating constructs failed through plate bending, screw cut-out or plate failure, whilst IMS failed via implant deformity. All three constructs required greater force to result in even 1 mm of displacement than what is likely subjected through rehabilitation via active motion. CONCLUSIONS: Lateral plating and IMS fixation offer sufficient stiffness to withstand the likely forces subjected via early active motion without displacement. CLINICAL RELEVANCE: Dorsal plating required significantly greater force than lateral plating and intramedullary screw fixation to achieve 1 mm of displacement when used in extra-articular proximal phalangeal fractures in an in vitro setting. However, all three modalities confer enough stability to likely withstand the forces associated with active range of motion.

Streamlining quantitative joint-wide medial femoro-tibial histopathological scoring of mouse post-traumatic knee osteoarthritis models.

OBJECTIVES: Histological scoring remains the gold-standard for quantifying post-traumatic osteoarthritis (ptOA) in animal models, allowing concurrent evaluation of numerous joint tissues. Available systems require scoring multiple sections/joint making analysis laborious and expensive. We investigated if a single section allowed equivalent quantitation of pathology in different joint tissues and disease stages, in three ptOA models. METHOD: Male 10-12-week-old C57BL/6 mice underwent surgical medial-meniscal-destabilization, anterior-cruciate-ligament (ACL) transection, non-invasive-ACL-rupture, or served as sham-surgical, non-invasive-ACL-strain, or naïve/non-operated controls. Mice (n = 12/group) were harvested 1-, 4-, 8-, and 16-week post-intervention. Serial sagittal toluidine-blue/fast-green stained sections of the medial-femoro-tibial joint (n = 7/joint, 84 µm apart) underwent blinded scoring of 40 histology-outcomes. We evaluated agreement between single-slide versus entire slide-set maximum or median scores (weighted-kappa), and sensitivity/specificity of single-slide versus median/maximum to detect OA pathology. RESULTS: A single optimal mid-sagittal section showed excellent agreement with median (weighted-kappa 0.960) and maximum (weighted-kappa 0.926) scores. Agreement for individual histology-outcomes was high with only 19/240 median and 15/240 maximum scores having a weighted-kappa ≤0.4, the majority of these (16/19 and 11/15) in control groups. Statistically-significant histology-outcome differences between ptOA models and their controls detected with the entire slide-set were reliably reproduced using a single slide (sensitivity >93.15%, specificity >93.10%). The majority of false-negatives with single-slide scoring were meniscal and subchondral bone histology-outcomes (89%) and occurred in weeks 1-4 post-injury (84%). CONCLUSION: A single mid-sagittal slide reduced the time needed to score diverse histopathological changes by 87% without compromising the sensitivity or specificity of the analysis, across a variety of ptOA models and time-points.

The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.

A Biomechanical Comparison of Different Suture Materials Used for Arthroscopic Shoulder Procedures.

PURPOSE: To evaluate the viscoelastic properties of 4 commercially available cord-like sutures and 2 commercially available suture tapes when subjected to physiological loads, as well as to compare them with each other and to identify the clinically most desirable combination of suture material properties. METHODS: Six suture materials (Ethibond, FiberWire, FiberTape, Orthocord, Ultrabraid, and Ultratape) underwent creep testing (n = 7, 60 N, 10 minutes) to determine specimen stiffness, initial elongation at 60 N of load, static creep (during 10 minutes of loading), and relaxed elongation (material recovery 3 minutes after removal of load). Furthermore, cyclic testing (n = 7, 10-45 N, 0.5 Hz, 500 cycles) was carried out to determine dynamic creep, peak-to-peak displacement, and relaxed elongation. Mechanical testing was conducted on a material testing machine in 37°C phosphate-buffered saline solution. RESULTS: FiberTape showed the greatest stiffness (23.9 ± 3.2 N/mm, P < .001), the smallest amounts of static (0.38 ± 0.10 mm, P < .001) and dynamic (0.16 ± 0.09 mm, P = .003) creep, and the smallest peak-to-peak displacement (0.20 ± 0.02 mm, P < .001). FiberTape and FiberWire showed the smallest initial elongation (1.17 ± 0.17 mm and 1.63 ± 0.25 mm, respectively; P < .001). Ultrabraid showed the greatest relaxed elongation, both statically (4.73 ± 0.73 mm, P < .001) and dynamically (4.18 ± 0.83 mm, P = .002). CONCLUSIONS: FiberTape consistently displayed less creep, greater stiffness, and less extensibility than the other suture types. Ultrabraid showed the largest amount of relaxed elongation on both static and dynamic testing. CLINICAL RELEVANCE: When considering high stiffness in combination with low initial extension and low static creep to be ideal parameters to achieve optimal initial construct stability and considering low dynamic creep in combination with low peak-to-peak displacement to be ideal conditions for the repetitive loading of the construct during the healing process, tapes seem to be superior to cord-like sutures for performing rotator cuff repair.

The impact of work-related stress on medication errors in Eastern Region Saudi Arabia.

OBJECTIVE: To examine the relationship between overall level and source-specific work-related stressors on medication errors rate. DESIGN: A cross-sectional study examined the relationship between overall levels of stress, 25 source-specific work-related stressors and medication error rate based on documented incident reports in Saudi Arabia (SA) hospital, using secondary databases. SETTING: King Abdulaziz Hospital in Al-Ahsa, Eastern Region, SA. PARTICIPANTS: Two hundred and sixty-nine healthcare professionals (HCPs). MAIN OUTCOME MEASURES: The odds ratio (OR) and corresponding 95% confidence interval (CI) for HCPs documented incident report medication errors and self-reported sources of Job Stress Survey. RESULTS: Multiple logistic regression analysis identified source-specific work-related stress as significantly associated with HCPs who made at least one medication error per month (P < 0.05), including disruption to home life, pressure to meet deadlines, difficulties with colleagues, excessive workload, income over 10 000 riyals and compulsory night/weekend call duties either some or all of the time. Although not statistically significant, HCPs who reported overall stress were two times more likely to make at least one medication error per month than non-stressed HCPs (OR: 1.95, P = 0.081). CONCLUSION: This is the first study to use documented incident reports for medication errors rather than self-report to evaluate the level of stress-related medication errors in SA HCPs. Job demands, such as social stressors (home life disruption, difficulties with colleagues), time pressures, structural determinants (compulsory night/weekend call duties) and higher income, were significantly associated with medication errors whereas overall stress revealed a 2-fold higher trend.

Snus: a compelling harm reduction alternative to cigarettes.

Snus is an oral smokeless tobacco product which is usually placed behind the upper lip, either in a loose form or in portioned sachets, and is primarily used in Sweden and Norway. The purpose of this review is to examine the reported effects of snus use in relation to specified health effects, namely lung cancer, cardiovascular disease, pancreatic cancer, diabetes, oral cancer and non-neoplastic oral disease. The review also examines the harm reduction potential of snus as an alternative to cigarettes by comparing the prevalence of snus use and cigarette smoking, and the reported incidence of tobacco-related diseases across European Union countries. The scientific literature generally indicates that the use of snus is not a significant risk factor for developing lung cancer, cardiovascular disease, pancreatic cancer or oral cancer. Studies investigating snus use and diabetes have reported that high consumption of snus (estimated as being four or more cans per week) may be associated with a higher risk of developing diabetes or components of metabolic syndrome; however, overall results are not conclusive. Snus use is associated with the presence of non-neoplastic oral mucosal lesions which are reported to heal rapidly once use has stopped. The most recent Eurobarometer data from 2017 reported that Sweden had the lowest prevalence of daily cigarette use in the European Union at 5% whilst daily "oral tobacco" use was reported to be 20%. European data published by the World Health Organisation in 2018 indicated that Sweden had the lowest rate of tobacco-related mortality and the lowest incidence of male lung cancer. Overall, prevalence statistics and epidemiological data indicate that the use of snus confers a significant harm reduction benefit which is reflected in the comparatively low levels of tobacco-related disease in Sweden when compared with the rest of Europe. The available scientific data, including long-term population studies conducted by independent bodies, demonstrates that the health risks associated with snus are considerably lower than those associated with cigarette smoking.

The Effect of Extensor Tendon Adhesions on Finger Motion.

PURPOSE: To quantify the amount and pattern of finger range of motion loss at the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints with a simulated extensor tendon adhesion at the level of the proximal phalanx or metacarpal. METHODS: In 10 cadaveric specimens, traction sutures were placed in the forearm extensor digitorum communis and flexor digitorum profundus tendons of the middle and ring fingers. Active motion was simulated by suspending weights from the traction sutures via pulleys. The angles of the MCP, PIP, and DIP joints were measured at the position of maximum flexion and extension. Extensor tendon adhesions were simulated alternately at the proximal phalanx and metacarpal levels of the middle and ring fingers, using suture anchors. Repeat measurements were taken using the same amount of force. RESULTS: There was an average total loss of flexion of 38° and of extension of 6° with a proximal phalanx adhesion, with a greater contribution of flexion loss at the PIP joint. The loss of flexion was 17° and of extension was 50° with a metacarpal adhesion, with a loss of extension mostly at the MCP joint. CONCLUSIONS: The results of this study identified clear patterns of motion loss that are associated with isolated simulated adhesions in different locations along the extensor mechanism. The greatest motion loss occurred at the joint immediately distal to the simulated adhesion. CLINICAL RELEVANCE: Although extrapolation of these findings to clinical relevance remains unclear, the ability to predict the level of adhesion by the pattern of motion restriction may allow for a targeted tenolysis procedure. This would reduce the amount of soft tissue dissection required, which in turn, could be expected to reduce the degree of repeat adhesion formation.

Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside.

Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. Such beneficial effects have made APC an attractive target of research in a plethora of physiological and pathophysiological processes. Of note, the past decade or so has seen the emergence of its roles in cutaneous wound healing-a complex process involving inflammation, proliferation and remodelling. This review will highlight APC's functions and mechanisms, and detail its pre-clinical and clinical studies on cutaneous wound healing.

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group.

The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Group's (AWG) protocol for evidence synthesis and semi-quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.

Cellular, matrix, and mechano-biological differences in load-bearing versus positional tendons throughout development and aging: a narrative review.

PURPOSE: Summarise available evidence comparing the cellular, biochemical, structural and biomechanical properties, and the changes that occur in these parameters in response to stimuli, in differentially loaded tendons across different stages of life. METHODS: The PubMed database was searched for literature pertaining to differences between tendons using the term "tendon" or "tendinopathy", plus one or more of the following descriptors: "loading", "positional", "weight- or load-bearing", and "energy-storing". The abstracts were reviewed and relevant full-length articles retrieved and used to assemble a narrative review. RESULTS: The incidence and prevalence of tendon disorders ("tendinopathies") is increasing in Western societies, with limited evidence that currently available treatments have any significant long-term effect on the disease course. A key emerging hypothesis is that disease in different tendons and even different regions within a tendon may be distinct. The available literature indicates that there are phenotypic differences, not only in the constitutive compositional and material properties but also in resident cells of positional compared with load-bearing tendons. Evident during early tendon growth, such differences have become well established by adulthood. CONCLUSIONS: The pheno-endotype of tendinopathy may be distinct between load-bearing tendons compared to positional tendons, which has translational implications with regard to preventing and managing tendinopathy. Better understanding of the molecular, cellular, and biomechanical pathophysiology underlying disease phenotypes, will allow more targeted/personalised treatment and therefore improve outcomes.

Effects of Removal and Reinsertion of Headless Compression Screws.

PURPOSE: This study investigates the loss of compression when 3 commonly used headless compression screws are backed out (reversed), and assesses the ability to re-establish compression with screws of greater diameter. METHODS: Two investigators tested 3 screw designs (Acutrak 2, Synthes HCS, Medartis SpeedTip CCS) in 2 diameters and lengths. Each design had 10 test cycles in a polyurethane foam bone model with compression recorded using a washer load cell. A 28-mm screw of the narrower diameter was inserted until 2 mm recessed and then reversed 30°, 60°, 90°, 180°, 270°, 360°, and 720°. After this the screw was removed completely and a 24-mm screw of greater diameter inserted until recessed 2 mm with the compressive force again recorded. RESULTS: All screws showed an immediate, statistically significant loss of compression at 30° of reversing. The Acutrak 2 Micro screw demonstrated not only the greatest mean compressive force, but also the fastest compressive loss. Insertion of the shorter screw of greater diameter was associated with re-establishment of compression to levels comparable with the original screw. CONCLUSIONS: This study reaffirms the importance of establishing the correct screw length before insertion due to the immediate loss of compression with reversal of these devices. CLINICAL RELEVANCE: If a headless compression screw penetrates the far joint surface, the screw should be completely removed and replaced with a shorter screw of greater diameter.

Quality of harness fit for normal and low birthweight infants observed among newborns in infant car seats.

INTRODUCTION: Child restraint fit is important for crash protection. For newborns, standards universally require a rear-facing restraint and some upper limit on size, but historically there has been no specification of a lower design limit and there is concern over whether low birthweight infants (LBW) are adequately restrained. The aim of this study was to determine the quality of harness fit for newborns of low and normal weight in a range of modern child restraints. METHODS: A convenience sample of infants (1.657-4.455 kg) were recruited from the postnatal ward and special care nursery <1 week from discharge. Infants (n=84) were assessed for harness fit in rear-facing-only restraints, convertible rear/forward restraints and a subset were assessed in a restraint specifically designed to accommodate LBW infants. Measures of harness fit were based on shoulder strap, crotch strap and buckle positioning. RESULTS: Less than 20% of infants achieved good harness fit, regardless of whether they were categorised as low (<2.5 kg) or normal weight. Rear-facing-only restraints were less likely to provide good fit than convertible restraints, in all measures of fit other than shoulder strap width. The proportions of infants achieving good fit were greater in the restraint designed for LBW infants than other restraint types. CONCLUSION: Poor accommodation continues to be a problem for LBW infants but is rectified in specifically designed restraints. Better specification of harness configuration for all rearward-facing restraints may be required to ensure adequate accommodation of normal birthweight infants.

Inflammation in Chronic Wounds.

Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, pressure, and diabetic ulcers) can be examined through a juxtaposition of normal healing and the rogue inflammatory response created by the common components within chronic wounds (ageing, hypoxia, ischaemia-reperfusion injury, and bacterial colonisation). Wound bed care through debridement, dressings, and antibiotics currently form the basic mode of treatment. Despite recent setbacks, pharmaceutical adjuncts form an interesting area of research.

Real-time imaging of Toxoplasma-infected human monocytes under fluidic shear stress reveals rapid translocation of intracellular parasites across endothelial barriers.

Peripheral blood monocytes are actively infected by Toxoplasma gondii and can function as 'Trojan horses' for parasite spread in the bloodstream. Using dynamic live-cell imaging, we visualized the transendothelial migration (TEM) of T. gondii-infected primary human monocytes during the initial minutes following contact with human endothelium. On average, infected and uninfected monocytes required only 9.8 and 4.1 min, respectively, to complete TEM. Infection increased monocyte crawling distances and velocities on endothelium, but overall TEM frequencies were comparable between infected and uninfected cells. In the vasculature, monocytes adhere to endothelium under the conditions of shear stress found in rapidly flowing blood. Remarkably, the addition of fluidic shear stress increased the TEM frequency of infected monocytes 4.5-fold compared to static conditions (to 45.2% from 10.3%). Infection led to a modest increase in expression of the high-affinityconformation of the monocyte integrin Mac-1 (CD11b/CD18), and Mac-1 accumulated near endothelial junctions during TEM. Blocking Mac-1 inhibited the crawling and TEM of infected monocytes to a greater degree than uninfected monocytes, and blocking the Mac-1 ligand, ICAM-1, dramatically reduced crawling and TEM for both populations. These findings contribute to a greater understanding of parasite dissemination from the vasculature into tissues.

Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells.

Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. In this study, we developed an autologous system using primary human lymphocytes and human monocyte-derived macrophages (HMDMs) to characterize the effect of C1q on macrophage gene expression profiles during the uptake of apoptotic cells. C1q bound to autologous apoptotic lymphocytes modulated expression of genes associated with JAK/STAT signaling, chemotaxis, immunoregulation, and NLRP3 inflammasome activation in LPS-stimulated HMDMs. Specifically, C1q sequentially induced type I IFNs, IL-27, and IL-10 in LPS-stimulated HMDMs and IL-27 in HMDMs when incubated with apoptotic lymphocyte conditioned media. Coincubation with C1q tails prevented the induction of type I IFNs and IL-27 in a dose-dependent manner, and neutralization of type I IFNs partially prevented IL-27 induction by C1q. Finally, C1q decreased procaspase-1 cleavage and caspase-1-dependent cleavage of IL-1ß suggesting a potent inhibitory effect of C1q on inflammasome activation. These results identify specific molecular pathways induced by C1q to suppress macrophage inflammation and provide potential therapeutic targets to control macrophage polarization and thus inflammation and autoimmunity.

Considerations for Glycoprotein Production.

This chapter is intended to provide insights for researchers aiming to choose an appropriate expression system for the production of recombinant glycoproteins. Producing glycoproteins is complex, as glycosylation patterns are determined by the availability and abundance of specific enzymes rather than a direct genetic blueprint. Furthermore, the cell systems often employed for protein production are evolutionarily distinct, leading to significantly different glycosylation when utilized for glycoprotein production. The selection of an appropriate production system depends on the intended applications and desired characteristics of the protein. Whether the goal is to produce glycoproteins mimicking native conditions or to intentionally alter glycan structures for specific purposes, such as enhancing immunogenicity in vaccines, understanding glycosylation present in the different systems and in different growth conditions is essential. This chapter will cover Escherichia coli, baculovirus/insect cell systems, Pichia pastoris, as well as different mammalian cell culture systems including Chinese hamster ovary (CHO) cells, human endothelial kidney (HEK) cell lines, and baby hamster kidney (BHK) cells.

Tendon biomechanical properties are altered by storage duration but not freeze-thaw temperatures or cycles.

Tendon allograft and xenograft processing often involves one or more steps of freezing and thawing. As failure strength is an important graft consideration, this study aimed to evaluate effects on failure properties when varying freeze-thaw conditions. Kangaroo tendons, a potential xenograft source, were used to evaluate changes in ultimate tensile strength (UTS), failure strain and elastic modulus after exposure to different freezer-storage temperatures (-20°C vs. -80°C), storage durations (1, 3, 6, 9, or 12 months), number of freeze-thaw cycles (1, 2, 3, 4, 5, or 10), or freeze-thaw temperature ranges (including freezing in liquid nitrogen to thawing at 37°C). Tendons stored for 6 or more months had significantly increased UTS and elastic modulus compared with 1 or 3 months of storage. This increase occurred irrespective of the freezing temperature (-20°C vs. -80°C) or the number of freeze-thaw cycles (1 vs. 10). In contrast, UTS, failure strain and the elastic modulus were no different between storage temperatures, number of freeze-thaw cycles and multiple freeze-thaw cycles across a range of freeze and thaw temperatures. Common freeze-thaw protocols did not negatively affect failure properties, providing flexibility for graft testing, storage, transportation and decellularisation procedures. However, the change in properties with the overall storage duration has implications for assessing the consistent performance of grafts stored for short versus extended periods of time (<6 months vs. >6 months), and the interpretation of data obtained from tissues of varying or unknown storage durations.

The Biomechanical, Biochemical, and Morphological Properties of 19 Human Cadaveric Lower Limb Tendons and Ligaments: An Open-Access Data Set.

BACKGROUND: Methodological heterogeneity hinders data comparisons across isolated studies of tendon and ligament properties, limiting clinical understanding and affecting the development and evaluation of replacement materials. PURPOSE: To create an open-access data set on the morphological, biomechanical, and biochemical properties of clinically important tendons and ligaments of the lower limb, using consistent methodologies, to enable direct tendon/ligament comparisons. STUDY DESIGN: Descriptive laboratory study. METHODS: Nineteen distinct lower limb tendons and ligaments were retrieved from 8 fresh-frozen human cadavers (5 male, 3 female; aged 49-65 years) including Achilles, tibialis posterior, tibialis anterior, fibularis (peroneus) longus, fibularis (peroneus) brevis, flexor hallucis longus, extensor hallucis longus, plantaris, flexor digitorum longus, quadriceps, patellar, semitendinosus, and gracilis tendons; anterior cruciate, posterior cruciate, medial collateral, and lateral collateral ligaments; and 10 mm-wide grafts from the contralateral quadriceps and patellar tendons. Outcomes included morphology (tissue length, ultrasound-quantified cross-sectional area [CSAUS], and major and minor axes), biomechanics (failure load, ultimate tensile strength [UTS], failure strain, and elastic modulus), and biochemistry (sulfated glycosaminoglycan [sGAG] and hydroxyproline contents). Tissue differences were analyzed using mixed-model regression. RESULTS: There was a range of similarities and differences between tendons and ligaments across outcomes. A key finding relating to potential graft tissue suitability was the comparable failure loads, UTS, CSAUS, sGAG, and hydroxyproline present between hamstring tendons (a standard graft source) and 5 tendons not typically used for grafting: fibularis (peroneus) longus and brevis, flexor and extensor hallucis longus, and flexor digitorum longus tendons. CONCLUSION: This study of lower limb tendons and ligaments has enabled direct comparison of morphological, biomechanical, and biochemical human tissue properties-key factors in the selection of suitable graft tissues. This analysis has identified 6 potential new donor tissues with properties comparable to currently used grafts. CLINICAL RELEVANCE: This extensive data set reduces the need to utilize data from incompatible sources, which may aid surgical decisions (eg, evidence to expand the range of tendons considered suitable for use as grafts) and may provide congruent design inputs for new biomaterials and computational models. The complete data set has been provided to facilitate further investigations, with the capacity to expand the resource to include additional outcomes and tissues.

Broad antibody and T cell responses to Ebola, Sudan, and Bundibugyo ebolaviruses using mono- and multi-valent adjuvanted glycoprotein vaccines.

Currently, there are two approved vaccine regimens designed to prevent Ebola virus (EBOV) disease (EVD). Both are virus-vectored, and concerns about cold-chain storage and pre-existing immunity to the vectors warrant investigating additional vaccine strategies. Here, we have explored the utility of adjuvanted recombinant glycoproteins (GPs) from ebolaviruses Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) for inducing antibody (Ab) and T cell cross-reactivity. Glycoproteins expressed in insect cells were administered to C57BL/6 mice as free protein or bound to the surface of liposomes, and formulated with toll-like receptor agonists CpG and MPLA (agonists for TLR 9 and 4, respectively), with or without the emulsions AddaVax or TiterMax. The magnitude of Ab cross-reactivity in binding and neutralization assays, and T cell cross-reactivity in antigen recall assays, correlated with phylogenetic relatedness. While most adjuvants screened induced IgG responses, a combination of CpG, MPLA and AddaVax emulsion ("IVAX-1") was the most potent and polarized in an IgG2c (Th1) direction. Breadth was also achieved by combining GPs into a trivalent (Tri-GP) cocktail with IVAX-1, which did not compromise antibody responses to individual components in binding and neutralizing assays. Th1 signature cytokines in T cell recall assays were undetectable after Tri-GP/IVAX-1 administration, despite a robust IgG2c response, although administration of Tri-GP on lipid nanoparticles in IVAX-1 elevated Th1 cytokines to detectable levels. Overall, the data indicate an adjuvanted trivalent recombinant GP approach may represent a path toward a broadly reactive, deployable vaccine against EVD.

Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.

Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.