Tough Adhesive Hydrogel for Intraoral Adhesion and Drug Delivery.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are common chronic inflammatory conditions, manifesting as painful oral lesions that negatively affect patients' quality of life. Current treatment approaches are mainly palliative and often ineffective due to inadequate contact time of the therapeutic agent with the lesions. Here, we developed the Dental Tough Adhesive (DenTAl), a bioinspired adhesive patch with robust mechanical properties, capable of strong adhesion against diverse wet and dynamically moving intraoral tissues, and extended drug delivery of clobetasol-17-propionate, a first-line drug for treating OLP and RAS. DenTAl was found to have superior physical and adhesive properties compared to existing oral technologies, with ~2 to 100× adhesion to porcine keratinized gingiva and ~3 to 15× stretchability. Clobetasol-17-propionate incorporated into the DenTAl was released in a tunable sustained manner for at least 3 wk and demonstrated immunomodulatory capabilities in vitro, evidenced by reductions in several cytokines, including TNF-α, IL-6, IL-10, MCP-5, MIP-2, and TIMP-1. Our findings suggest that DenTAl may be a promising device for intraoral delivery of small-molecule drugs applicable to the management of painful oral lesions associated with chronic inflammatory conditions.

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

A novel tool to quantify in vivo lumbar spine kinematics and 3D intervertebral disc strains using clinical MRI.

Medical imaging modalities that calculate tissue morphology alone cannot provide direct information regarding the mechanical behaviour of load-bearing musculoskeletal organs. Accurate in vivo measurement of spine kinematics and intervertebral disc (IVD) strains can provide important information regarding the mechanical behaviour of the spine, help to investigate the effects of injuries on the mechanics of the spine, and assess the effectiveness of treatments. Additionally, strains can serve as a functional biomechanical marker for detecting normal and pathologic tissues. We hypothesised that combining digital volume correlation (DVC) with 3T clinical MRI can provide direct information regarding the mechanics of the spine. Here, we have developed a novel non-invasive tool for in vivo displacement and strain measurement within the human lumbar spine and we used this tool to calculate lumbar kinematics and IVD strains in six healthy subjects during lumbar extension. The proposed tool enabled spine kinematics and IVD strains to be measured with errors that did not exceed 0.17 mm and 0.5%, respectively. The findings of the kinematics study identified that during extension the lumbar spine of healthy subjects experiences total 3D translations ranging from 1 mm to 4.5 mm for different vertebral levels. The findings of strain analysis identified that the average of the maximum tensile, compressive, and shear strains for different lumbar levels during extension ranged from 3.5% to 7.2%. This tool can provide base-line data that can be used to describe the mechanical environment of healthy lumbar spine, which can help clinicians manage preventative treatments, define patient-specific treatments, and to monitor the effectiveness of surgical and non-surgical interventions.

Association between beta-blocker use and obesity in Hong Kong Chinese elders: a post-hoc analysis.

INTRODUCTION: Studies of Caucasian populations have shown that beta-blockers may exacerbate weight gain, a risk factor for many chronic diseases. Still, beta-blockers are the most prescribed antihypertensives in the Chinese population in Hong Kong. We aimed to explore the association between beta-blocker use, hypertension, and weight status of this population. METHODS: A post-hoc analysis regarding body mass index (BMI) and the use of beta-blockers was performed based on the medication profile of community-dwelling older adults. Participants' BMI, hypertension diagnosis, name, dose, frequency, route of administration of beta-blockers, and other drugs that may alter body weight were recorded. RESULTS: Of 1053 Chinese individuals aged ≥65 years (mean age 76.9±7.2 years, 80% female) from 32 elderly centres in Hong Kong, 18% (185/1053) of them consumed beta-blockers. That group also had a significantly larger proportion of obese individuals (45.9% vs 32.1%, P=0.002). After adjusting for other weight-altering drugs, beta-blockers remained a significant predictor of overweight and obesity (P=0.001). As the hypertensive population had significantly higher BMI than the normotensive population (24.3±3.6 vs 22.9±3.5, P<0.001), a sub-analysis on those with hypertension diagnosis confirmed that only the hypertensive population taking atenolol had a significantly larger population of obese individuals (BMI ≥25) compared with those who took metoprolol (58.9% vs 38.5%, P=0.03) and those who did not take any beta-blockers (58.9% vs 38.4%, P=0.007). CONCLUSIONS: Our findings taken together with other guideline reservations cast doubt on whether beta-blockers, particularly atenolol, should be the major drug prescribed to older adults with hypertension.

Bioinspired mechanically active adhesive dressings to accelerate wound closure.

Inspired by embryonic wound closure, we present mechanically active dressings to accelerate wound healing. Conventional dressings passively aid healing by maintaining moisture at wound sites. Recent developments have focused on drug and cell delivery to drive a healing process, but these methods are often complicated by drug side effects, sophisticated fabrication, and high cost. Here, we present novel active adhesive dressings consisting of thermoresponsive tough adhesive hydrogels that combine high stretchability, toughness, tissue adhesion, and antimicrobial function. They adhere strongly to the skin and actively contract wounds, in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in accelerating and supporting skin wound healing. Finite element models validate and refine the wound contraction process enabled by these active adhesive dressings. This mechanobiological approach opens new avenues for wound management and may find broad utility in applications ranging from regenerative medicine to soft robotics.

Psoas and Paraspinous Muscle Measurements on Computed Tomography Predict Mortality in European Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations. OBJECTIVES: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D). DESIGN: Single-center observational study. SETTING: Diabetes Heart Study. PARTICIPANTS: 839 European Americans with T2D. METHODS: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015. RESULTS: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p<0.001), psoas muscle index (HR 0.82, p=0.008), and paraspinous muscle density (HR 0.85, p=0.003) were inversely associated with mortality. Paraspinous muscle index was not significantly associated with mortality (HR 0.90, p=0.08). Results did not differ significantly between men and women. CONCLUSIONS: In addition to established risk factors for mortality and CVD, higher psoas muscle index, psoas muscle density, and paraspinous muscle density were significantly associated with lower all-cause mortality in European Americans with T2D.

Supraspinatus Tendons Have Different Mechanical Properties Across Sex.

Sex differences in the mechanical properties of different musculoskeletal tissues and their impact on tendon function and disease are becoming increasingly recognized. Tendon mechanical properties are influenced by the presence or absence of sex hormones and these effects appear to be tendon- or ligament-specific. The objective of this study was to determine how sex and hormone differences in rats affect supraspinatus tendon and muscle properties. We hypothesized that male supraspinatus tendons would have increased cross-sectional area but no differences in tendon material properties or muscle composition when compared to supraspinatus tendons from female or ovariectomized (OVX) female rats. Uninjured supraspinatus tendons and muscles from male, female, and OVX female rats were collected and mechanical and histological properties were determined. Our analysis demonstrated decreased dynamic modulus and increased hysteresis and cross-sectional area in male tendons. We found that male tendons exhibited decreased dynamic modulus (during low strain frequency sweep and high strain fatigue loading), increased hysteresis, and increased cross-sectional area compared to female and OVX female tendons. Despite robust mechanical differences, tendon cell density and shape, and muscle composition remained unchanged between groups. Interestingly, these differences were unique compared to previously reported sex differences in rat Achilles tendons, which further supports the concept that the effect of sex on tendon varies anatomically. These differences may partially provide a mechanistic explanation for the increased rate of acute supraspinatus tendon ruptures seen in young males.

Continual near-infrared spectroscopy monitoring in the injured lower limb and acute compartment syndrome: an FDA-IDE trial.

Aims: The aim of this study was to evaluate near-infrared spectroscopy (NIRS) as a continuous, non-invasive monitor for acute compartment syndrome (ACS). Patients and Methods: NIRS sensors were placed on 86 patients with, and 23 without (controls), severe leg injury. NIRS values were recorded for up to 48 hours. Longitudinal data were analyzed using summary and graphical methods, bivariate comparisons, and multivariable multilevel modelling. Results: Mean NIRS values in the anterior, lateral, superficial posterior, and deep posterior compartments were between 72% and 78% in injured legs, between 69% and 72% in uninjured legs, and between 71% and 73% in bilaterally uninjured legs. In patients without ACS, the values were typically > 3% higher in injured compartments. All seven limbs with ACS had at least one compartment where NIRS values were 3% or more below a reference uninjured control compartment. Missing data were encountered in many instances. Conclusion: NIRS oximetry might be used to aid the assessment and management of patients with ACS. Sustained hyperaemia is consistent with the absence of ACS in injured legs. Loss of the hyperaemic differential warrants heightened surveillance. NIRS values in at least one injured compartment(s) were > 3% below the uninjured contralateral compartment(s) in all seven patients with ACS. Additional interventional studies are required to validate the use of NIRS for ACS monitoring. Cite this article: Bone Joint J 2018;100-B:787-97.

The American Orthopaedic Association's Own the Bone® database: a national quality improvement project for the treatment of bone health in fragility fracture patients.

The American Orthopaedic Association initiated the Own the Bone (OTB) quality improvement program in 2009. Herein we show that the data collected through this program is similar to that collected in other large studies. Thus, the OTB registry functions as an externally valid cohort for studying fragility fracture patients. INTRODUCTION: The American Orthopedic Association initiated the Own the Bone (OTB) quality improvement program in 2009 to improve secondary prevention of fragility fractures. In this study, we present a summary of the data collected by the OTB program and compare it to data from other large fragility fracture registries with an aim to externally validate the OTB registry. METHODS: The OTB registry contained 35,038 unique cases of fragility fracture as of September, 2016. We report the demographics, presenting fracture characteristics, past fracture history, and bone mineral density (BMD) data and compare these to data from large fragility fracture studies across the world. RESULTS: Seventy-three percent of the patients in the OTB registry were female, Caucasian, and post-menopausal. In 54.4% of cases, patients had a hip fracture; spine fractures were the second most common fracture type occurring in 11.1% of patients. Thirty-four percent of the patients had a past history of fragility fracture, and the most common sites were the spine and hip. The average femoral neck T-score was - 2.06. When compared to other studies, the OTB database showed similar findings with regard to patient age, gender, race, BMI, BMD profile, prior fracture history, and family history of fragility fractures. CONCLUSION: OTB is the first and largest multi-center voluntary fragility fracture registry in the USA. The data collected through the OTB program is comparable to that collected in international studies. Thus, the OTB registry functions as an externally valid cohort for further studies assessing the clinical characteristics, interventions, and outcomes achieved in patients who present with a fragility fracture in the USA.

Volumetric bone mineral density of the spine predicts mortality in African-American men with type 2 diabetes.

The study showed that in African-American men with type 2 diabetes mellitus (T2D), vertebral volumetric bone mineral density (vBMD) predicts all-cause mortality, independent of other risk factors for death. INTRODUCTION: Compared to European Americans, African Americans have lower rates of osteoporosis and higher rates of T2D. The relationships between BMD and fractures with mortality are unknown in this population. The aim of this study was to determine relationships between vertebral fractures and vertebral vBMD and mortality in African Americans with T2D. METHODS: Associations between vertebral fractures and vBMD with all-cause mortality were examined in 675 participants with T2D (391 women and 284 men) in the African American-Diabetes Heart Study (AA-DHS). Lumbar and thoracic vBMD were measured using quantitative computed tomography (QCT). Vertebral fractures were assessed on sagittal CT images. Associations of vertebral fractures and vBMD with all-cause mortality were determined in sex-stratified analyses and in the full sample. Covariates in a minimally adjusted model included age, sex, BMI, smoking, and alcohol use; the full model was adjusted for those variables plus cardiovascular disease, hypertension, coronary artery calcified plaque, hormone replacement therapy (women), African ancestry proportion, and eGFR. RESULTS: After mean 7.6 ± 1.8-year follow-up, 59 (15.1%) of women and 58 (20.4%) of men died. In men, vBMD was inversely associated with mortality in the fully adjusted model: lumbar hazard ratio (HR) per standard deviation (SD) = 0.70 (95% CI 0.52-0.95, p = 0.02) and thoracic HR per SD = 0.71 (95% CI 0.54-0.92, p = 0.01). Only trends toward association between vBMD and mortality were observed in the combined sample of men and women, as significant associations were absent in women. Vertebral fractures were not associated with mortality in either sex. CONCLUSIONS: Lower vBMD was associated with increased all-cause mortality in African-American men with T2D, independent of other risk factors for mortality including subclinical atherosclerosis.

Aging leads to inferior Achilles tendon mechanics and altered ankle function in rodents.

Spontaneous rupture of the Achilles tendon is increasingly common in the middle aged population. However, the cause for the particularly high incidence of injury in this age group is not well understood. Therefore, the objective of this study was to identify age-specific differences in the Achilles tendon-muscle complex using an animal model. Functional measures were performed in vivo and tissues were harvested following euthanasia for mechanical, structural, and histological analysis from young, middle aged, and old rats. Numerous alterations in tendon properties were detected across age groups, including inferior material properties (maximum stress, modulus) with increasing age. Differences in function were also observed, as older animals exhibited increased ankle joint passive stiffness and decreased propulsion force during locomotion. Macroscale differences in tendon organization were not observed, although cell density and nuclear shape did vary between age groups. Muscle fiber size and type distribution were not notably affected by age, indicating that other factors may be more responsible for age-specific Achilles tendon rupture rates. This study improves our understanding of the role of aging in Achilles tendon biomechanics and ankle function, and helps provide a potential explanation for the disparate incidence of Achilles tendon ruptures in varying age groups.

Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index.

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.

Males have Inferior Achilles Tendon Material Properties Compared to Females in a Rodent Model.

The Achilles tendon is the most commonly ruptured tendon in the human body. Numerous studies have reported incidence of these injuries to be upwards of five times as common in men than women. Therefore, the objective of this study was to investigate the sex- and hormone-specific differences between Achilles tendon and muscle between female, ovariectomized female (ovarian hormone deficient), and male rats. Uninjured tissues were collected from all groups for mechanical, structural, and histological analysis. Our results showed that while cross-sectional area and failure load were increased in male tendons, female tendons exhibited superior tendon material properties and decreased muscle fiber size. Specifically, linear and dynamic moduli were increased while viscoelastic properties (e.g., hysteresis, percent relaxation) were decreased in female tendons, suggesting greater resistance to deformation under load and more efficient energy transfer, respectively. No differences were identified in tendon organization, cell shape, cellularity, or proteoglycan content. Additionally, no differences in muscle fiber type distribution were observed between groups. In conclusion, inferior tendon mechanical properties and increased muscle fiber size may explain the increased susceptibility for Achilles tendon injury observed clinically in men compared to women.

Ground reaction forces are more sensitive gait measures than temporal parameters in rodents following rotator cuff injury.

Gait analysis is a quantitative, non-invasive technique that can be used to investigate functional changes in animal models of musculoskeletal disease. Changes in ground reaction forces following injury have been observed that coincide with differences in tissue mechanical and histological properties during healing. However, measurement of these kinetic gait parameters can be laborious compared to the simpler and less time-consuming analysis of temporal gait parameters alone. We compared the sensitivity of temporal and kinetic gait parameters in detecting functional changes following rotator cuff injury in rats. Although these parameters were strongly correlated, temporal measures were unable to detect greater than 50% of the functional gait differences between injured and uninjured animals identified simultaneously by ground reaction forces. Regression analysis was used to predict ground reaction forces from temporal parameters. This model improved the ability of temporal parameters to identify known functional changes, but only when these differences were large in magnitude (i.e., between injured vs. uninjured animals, but not between different post-operative treatments). The results of this study suggest that ground reaction forces are more sensitive measures of limb/joint function than temporal parameters following rotator cuff injury in rats. Therefore, although gait analysis systems without force plates are typically efficient and easy to use, they may be most appropriate for use when major functional changes are expected.

Effects of Type 2 Diabetes on Brain Structure and Cognitive Function: African American-Diabetes Heart Study MIND.

BACKGROUND AND PURPOSE: Rates of type 2 diabetes are higher among African Americans compared with individuals of European ancestry. The purpose of this investigation was to determine the relationship between MR imaging measures of brain structure (volume of GM, WM, WM lesions) and cognitive function in a population of African Americans with type 2 diabetes. These MR imaging measures of brain structure are affected by type 2 diabetes-associated macrovascular and microvascular disease and may be associated with performance on tasks of cognitive function in the understudied African American population. MATERIALS AND METHODS: African Americans with type 2 diabetes enrolled in the African American-Diabetes Heart Study MIND study (n = 263) were evaluated across a broad range of cognitive domains and imaged with brain MR imaging. Associations between cognitive parameters and MR imaging measures of whole-brain GM, WM, and WM lesion volumes were assessed by using adjusted multivariate models. RESULTS: Lower GM volume was associated with poorer performance on measures of general cognitive function, working memory, and executive function. Higher WM lesion volume was associated with poorer performance on a smaller subset of cognitive domains compared with GM volume but included aspects of working memory and executive function. There were no statistically significant associations with WM volume. CONCLUSIONS: Markers of cortical atrophy and WM lesion volume are associated with cognitive function in African Americans with type 2 diabetes. These associations are described in an African American cohort with disease control similar to that of individuals of European ancestry, rather than underserved African Americans with poor access to health care. Interventions to reduce cortical atrophy and WM disease may improve cognitive outcomes in this understudied population.

Pleiotropic, heart rate-independent cardioprotection by ivabradine.

BACKGROUND AND PURPOSE: In pigs, ivabradine reduces infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of this non-heart rate-related cardioprotection is unknown. Hence, in the present study we assessed the pleiotropic action of ivabradine in more detail. EXPERIMENTAL APPROACH: Anaesthetized mice were pretreated with ivabradine (1.7 mg · kg(-1) i.v.) or placebo (control) before a cycle of coronary occlusion/reperfusion (30/120 min ± left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) in the absence and presence of ivabradine, viability was then quantified and intra- and extracellular reactive oxygen species (ROS) formation was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and ADP-containing buffer in the absence and presence of ivabradine respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial ATP production and calcium retention capacity (CRC) were assessed. KEY RESULTS: Ivabradine decreased infarct size even with atrial pacing. Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradine, the accumulation of intra- and extracellular ROS decreased in parallel. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS, increased mitochondrial ATP production and increased CRC. CONCLUSION AND IMPLICATIONS: Ivabradine reduces infarct size independently of a reduction in heart rate and improves ventricular cardiomyocyte viability, possibly by reducing mitochondrial ROS formation, increasing ATP production and CRC.

Achilles tendons from decorin- and biglycan-null mouse models have inferior mechanical and structural properties predicted by an image-based empirical damage model.

Achilles tendons are a common source of pain and injury, and their pathology may originate from aberrant structure function relationships. Small leucine rich proteoglycans (SLRPs) influence mechanical and structural properties in a tendon-specific manner. However, their roles in the Achilles tendon have not been defined. The objective of this study was to evaluate the mechanical and structural differences observed in mouse Achilles tendons lacking class I SLRPs; either decorin or biglycan. In addition, empirical modeling techniques based on mechanical and image-based measures were employed. Achilles tendons from decorin-null (Dcn(-/-)) and biglycan-null (Bgn(-/-)) C57BL/6 female mice (N=102) were used. Each tendon underwent a dynamic mechanical testing protocol including simultaneous polarized light image capture to evaluate both structural and mechanical properties of each Achilles tendon. An empirical damage model was adapted for application to genetic variation and for use with image based structural properties to predict tendon dynamic mechanical properties. We found that Achilles tendons lacking decorin and biglycan had inferior mechanical and structural properties that were age dependent; and that simple empirical models, based on previously described damage models, were predictive of Achilles tendon dynamic modulus in both decorin- and biglycan-null mice.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.