A Novel Approach to Assessing the Joint Effects of Mercury and Fish Consumption on Neurodevelopment in the New Bedford Cohort.

Understanding health risks from methylmercury (MeHg) exposure is complicated by its link to fish consumption which may confound or modify toxicities. One solution is to include fish intake and a biomarker of MeHg exposure in the same model, but resulting estimates do not reflect the independent impact of accumulated MeHg or fish exposures. In fish-eating populations, this can be addressed by separating MeHg exposure into fish intake and average Hg content of the consumed fish. We assessed the joint association of prenatal MeHg exposure (maternal hair Hg) and fish intake (among fish-eating mothers) with neurodevelopment in 361 eight-year-olds from the New Bedford Cohort (born 1993-1998). Neurodevelopmental assessments used standardized tests of IQ, language, memory, and attention. Covariate-adjusted regression assessed the association of maternal fish consumption, stratified by tertiles of estimated average fish Hg, with neurodevelopment. Associations between maternal fish intake and child outcomes were generally beneficial for those in the lowest average fish Hg tertile, but detrimental in the highest average fish Hg tertile where, for example, each serving of fish was associated with 1.3 fewer correct responses (95% CI: -2.2, -0.4) on the Boston Naming test. Standard analyses showed no outcome associations with hair Hg or fish intake.

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogenous disease characterized by unexplained persistent fatigue and other features including cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Cytokines are present in plasma and encapsulated in extracellular vesicles (EVs), but there have been only a few reports of EV characteristics and cargo in ME/CFS. Several small studies have previously described plasma proteins or protein pathways that are associated with ME/CFS. METHODS: We prepared extracellular vesicles (EVs) from frozen plasma samples from a cohort of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) cases and controls with prior published plasma cytokine and plasma proteomics data. The cytokine content of the plasma-derived extracellular vesicles was determined by a multiplex assay and differences between patients and controls were assessed. We then performed multi-omic statistical analyses that considered not only this new data, but extensive clinical data describing the health of the subjects. RESULTS: ME/CFS cases exhibited greater size and concentration of EVs in plasma. Assays of cytokine content in EVs revealed IL2 was significantly higher in cases. We observed numerous correlations among EV cytokines, among plasma cytokines, and among plasma proteins from mass spectrometry proteomics. Significant correlations between clinical data and protein levels suggest roles of particular proteins and pathways in the disease. For example, higher levels of the pro-inflammatory cytokines Granulocyte-Monocyte Colony-Stimulating Factor (CSF2) and Tumor Necrosis Factor (TNFα) were correlated with greater physical and fatigue symptoms in ME/CFS cases. Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS. Machine learning classifiers were able to identify a list of 20 proteins that could discriminate between cases and controls, with XGBoost providing the best classification with 86.1% accuracy and a cross-validated AUROC value of 0.947. Random Forest distinguished cases from controls with 79.1% accuracy and an AUROC value of 0.891 using only 7 proteins. CONCLUSIONS: These findings add to the substantial number of objective differences in biomolecules that have been identified in individuals with ME/CFS. The observed correlations of proteins important in immune responses and hemostasis with clinical data further implicates a disturbance of these functions in ME/CFS.

A semiparametric risk score for physical activity.

We develop a generalized partially additive model to build a single semiparametric risk scoring system for physical activity across multiple populations. A score comprised of distinct and objective physical activity measures is a new concept that offers challenges due to the nonlinear relationship between physical behaviors and various health outcomes. We overcome these challenges by modeling each score component as a smooth term, an extension of generalized partially linear single-index models. We use penalized splines and propose two inferential methods, one using profile likelihood and a nonparametric bootstrap, the other using a full Bayesian model, to solve additional computational problems. Both methods exhibit similar and accurate performance in simulations. These models are applied to the National Health and Nutrition Examination Survey and quantify nonlinear and interpretable shapes of score components for all-cause mortality.

Poly(lactide-co-ε-caprolactone) scaffold promotes equivalent tissue integration and supports skin grafts compared to a predicate collagen scaffold.

Dermal scarring from motor vehicle accidents, severe burns, military blasts, etc. is a major problem affecting over 80 million people worldwide annually, many of whom suffer from debilitating hypertrophic scar contractures. These stiff, shrunken scars limit mobility, impact quality of life, and cost millions of dollars each year in surgical treatment and physical therapy. Current tissue engineered scaffolds have mechanical properties akin to unwounded skin, but these collagen-based scaffolds rapidly degrade over 2 months, premature to dampen contracture occurring 6-12 months after injury. This study demonstrates a tissue engineered scaffold can be manufactured from a slow-degrading viscoelastic copolymer, poly(ι-lactide-co-ε-caprolactone), with physical and mechanical characteristics to promote tissue ingrowth and support skin-grafts. Copolymers were synthesized via ring-opening polymerization. Solvent casting/particulate leaching was used to manufacture 3D porous scaffolds by mixing copolymers with particles in an organic solvent followed by casting into molds and subsequent particle leaching with water. Scaffolds characterized through SEM, micro-CT, and tensile testing confirmed the required thickness, pore size, porosity, modulus, and strength for promoting skin-graft bioincorporation and dampening fibrosis in vivo. Scaffolds were Oxygen Plasma Treatment and collagen coated to encourage cellular proliferation. Porosity ranging from 70% to 90% was investigated in a subcutaneous murine model and found to have no clinical effect on tissue ingrowth. A swine full-thickness skin wound model confirmed through histology and Computer Planimetry that scaffolds promote skin-graft survival, with or without collagen coating, with equal safety and efficacy as a commercially available tissue engineered scaffold. This study validates a scalable method to create poly(ι-lactide-co-ε-caprolactone) scaffolds with appropriate characteristics and confirms in mouse and swine wound models that the scaffolds are safe and effective at supporting skin-grafts. The results of this study have brought us closer towards developing an alternative technology that supports skin grafts with the potential to investigate long-term hypertrophic scar contractures.

Osteogenic benefits of low-intensity pulsed ultrasound and vibration in a rodent osseointegration model.

OBJECTIVES: Osseointegrated prostheses are increasingly used for amputees, however, the lengthy rehabilitation time of these prostheses remains a challenge to their implementation. The aim of this study was to investigate the ability of locally applied vibration or low-intensity pulsed ultrasound (LIPUS) to accelerate osseointegration and increase peri-implant bone volume. METHODS: A 4-week and 8-week rodent study were conducted in a femoral intramedullary implant model (control, vibration, LIPUS, and combined treatment) to determine effects on healing. Osseointegration was evaluated quantitatively through mechanical, µCT and histological evaluations. RESULTS: Maximum pushout load at 4 weeks increased with LIPUS relative to control (37.7%, P=0.002). Histologically, LIPUS and vibration separately increased peri-implant bone formation after 4 weeks relative to control. Vibration resulted in greater peri-implant bone after 8 weeks than all other groups (25.7%, P<0.001). However, no significant group differences in pushout load were noted at 8 weeks. CONCLUSIONS: Although vibration increased bone around implants, LIPUS was superior to vibration for accelerating osseointegration and increasing bone-implant failure loads at 4 weeks. However, the LIPUS benefits on osseointegration at 4 weeks were not sustained at 8 weeks.

Bone changes after short-term whole body vibration are confined to cancellous bone.

OBJECTIVE: This study assessed femur properties in 80 adult female rats exposed to a range of whole body vibration amplitudes at 45 Hz over five weeks. Our hypothesis was that an optimal amplitude for whole body vibration would be apparent and would result in increased bone strength. METHODS: Animals were treated in five amplitude groups (0 g, 0.15 g, 0.3 g, 0.6 g, and 1.2 g peak), for 15 minutes per day, five days per week, for five weeks. Femur strength was assessed via: (1) three-point bending of the shaft, (2) cantilever bending of the neck, and (3) indentation of distal cancellous bone. Femoral bone mineral density, plasma prostaglandin E2 (PGE2) concentrations, cartilage thickness, and histopathologic properties were measured. RESULTS: Vibration doubled (P=0.039) cancellous bone stiffness in the 0.6 g and 1.2 g groups and induced a 74% increase in PGE2 concentrations (P=0.007). However, femoral densitometry and strength of the neck and shaft were unchanged and the cancellous bone indentation strength did not differ statistically (P=0.084). Cartilage thickness of vibrated groups at the medial condyle did not increase significantly (P=0.142) and the histopathologic grade did not change. There was no definitive optimal vibration amplitude. CONCLUSION: The benefits of vibration therapy over five weeks were confined to cancellous bone.

Hydrology and Soil Manipulations of Iron-Rich Ditch Mesocosms Provide Little Evidence of Phosphorus Capture within the Profile.

Agricultural drainage ditches function as first-order streams and affect nutrient management. Soil mesocosms from a ditch featuring a vertical (increasing upward) gradient in iron (Fe) and phosphorus (P) were subjected to hydraulic and soil treatments. These manipulations mimicked aspects of dredging and controlled drainage and inspected the soil release and retention of P. Treatments did not remove P from simulated groundwater. Throughput water either gained in P (lack of dredging, especially under Fe-reducing conditions) or had P concentrations indistinguishable from input water (dredging). Undredged mesocosms, when Fe-reducing, released Fe and P simultaneously. Simultaneous release of P and Fe from our Fe-reducing mesocosms indicates a mechanism whereby P capture occurs by Fe precipitation upon emergence to aerated surficial waters. Upwelling and surficial phases of ditch hydrology and the lowering of the ditch surface on dredging complicate interpretation of traditional means of describing ditch P retention and release.

Spatiotemporal mixed modeling of multi-subject task fMRI via method of moments.

Estimating spatiotemporal models for multi-subject fMRI is computationally challenging. We propose a mixed model for localization studies with spatial random effects and time-series errors. We develop method-of-moment estimators that leverage population and spatial information and are scalable to massive datasets. In simulations, subject-specific estimates of activation are considerably more accurate than the standard voxel-wise general linear model. Our mixed model also allows for valid population inference. We apply our model to cortical data from motor and theory of mind tasks from the Human Connectome Project (HCP). The proposed method results in subject-specific predictions that appear smoother and less noisy than those from the popular single-subject univariate approach. In particular, the regions of motor cortex associated with a left-hand finger-tapping task appear to be more clearly delineated. Subject-specific maps of activation from task fMRI are increasingly used in pre-surgical planning for tumor removal and in locating targets for transcranial magnetic stimulation. Our findings suggest that using spatial and population information is a promising avenue for improving clinical neuroimaging.

An evaluation of independent component analyses with an application to resting-state fMRI.

We examine differences between independent component analyses (ICAs) arising from different assumptions, measures of dependence, and starting points of the algorithms. ICA is a popular method with diverse applications including artifact removal in electrophysiology data, feature extraction in microarray data, and identifying brain networks in functional magnetic resonance imaging (fMRI). ICA can be viewed as a generalization of principal component analysis (PCA) that takes into account higher-order cross-correlations. Whereas the PCA solution is unique, there are many ICA methods-whose solutions may differ. Infomax, FastICA, and JADE are commonly applied to fMRI studies, with FastICA being arguably the most popular. Hastie and Tibshirani (2003) demonstrated that ProDenICA outperformed FastICA in simulations with two components. We introduce the application of ProDenICA to simulations with more components and to fMRI data. ProDenICA was more accurate in simulations, and we identified differences between biologically meaningful ICs from ProDenICA versus other methods in the fMRI analysis. ICA methods require nonconvex optimization, yet current practices do not recognize the importance of, nor adequately address sensitivity to, initial values. We found that local optima led to dramatically different estimates in both simulations and group ICA of fMRI, and we provide evidence that the global optimum from ProDenICA is the best estimate. We applied a modification of the Hungarian (Kuhn-Munkres) algorithm to match ICs from multiple estimates, thereby gaining novel insights into how brain networks vary in their sensitivity to initial values and ICA method.

Anti-adhesive bioresorbable elastomer-coated composite hernia mesh that reduce intraperitoneal adhesions.

Intraperitoneal adhesions (IAs) are a major complication arising from abdominal repair surgeries, including hernia repair procedures. Herein, we fabricated a composite mesh device using a macroporous monofilament polypropylene mesh and a degradable elastomer coating designed to meet the requirements of this clinical application. The degradable elastomer was synthesized using an organo-base catalyzed thiol-yne addition polymerization that affords independent control of degradation rate and mechanical properties. The elastomeric coating was further enhanced by the covalent tethering of antifouling zwitterion molecules. Mechanical testing demonstrated the elastomer forms a robust coating on the polypropylene mesh does not exhibit micro-fractures, cracks or mechanical delamination under cyclic fatigue testing that exceeds peak abdominal loads (50 N/cm). Quartz crystal microbalance measurements showed the zwitterionic functionalized elastomer further reduced fibrinogen adsorption by 73% in vitro when compared to unfunctionalized elastomer controls. The elastomer exhibited degradation with limited tissue response in a 10-week murine subcutaneous implantation model. We also evaluated the composite mesh in an 84-day study in a rabbit cecal abrasion hernia adhesion model. The zwitterionic composite mesh significantly reduced the extent and tenacity of IAs by 94% and 90% respectively with respect to uncoated polypropylene mesh. The resulting composite mesh device is an excellent candidate to reduce complications related to abdominal repair through suppressed fouling and adhesion formation, reduced tissue inflammation, and appropriate degradation rate.

Modeling functional data with spatially heterogeneous shape characteristics.

We propose a novel class of models for functional data exhibiting skewness or other shape characteristics that vary with spatial or temporal location. We use copulas so that the marginal distributions and the dependence structure can be modeled independently. Dependence is modeled with a Gaussian or t-copula, so that there is an underlying latent Gaussian process. We model the marginal distributions using the skew t family. The mean, variance, and shape parameters are modeled nonparametrically as functions of location. A computationally tractable inferential framework for estimating heterogeneous asymmetric or heavy-tailed marginal distributions is introduced. This framework provides a new set of tools for increasingly complex data collected in medical and public health studies. Our methods were motivated by and are illustrated with a state-of-the-art study of neuronal tracts in multiple sclerosis patients and healthy controls. Using the tools we have developed, we were able to find those locations along the tract most affected by the disease. However, our methods are general and highly relevant to many functional data sets. In addition to the application to one-dimensional tract profiles illustrated here, higher-dimensional extensions of the methodology could have direct applications to other biological data including functional and structural magnetic resonance imaging (MRI).

Paramedics experiences and expectations concerning advance directives: a prospective, questionnaire-based, bi-centre study.

BACKGROUND: Advance directives and palliative crisis cards are means by which palliative care patients can exert their autonomy in end-of-life decisions. AIM: To examine paramedics' attitudes towards advance directives and end-of-life care. DESIGN: Questionnaire-based investigation using a self-administered survey instrument. SETTING/PARTICIPANTS: Paramedics of two cities (Hamburg and Goettingen, Germany) were included. Participants were questioned as to (1) their attitudes about advance directives, (2) their clinical experiences in connection with end-of-life situations (e.g. resuscitation), (3) their suggestions in regard to advance directives, 'Do not attempt resuscitation' orders and palliative crisis cards. RESULTS: Questionnaires were returned by 728 paramedics (response rate: 81%). The majority of paramedics (71%) had dealt with advance directives and end-of-life decisions in emergency situations. Most participants (84%) found that cardiopulmonary resuscitation in end-of-life patients is not useful and 75% stated that they would withhold cardiopulmonary resuscitation in the case of legal possibility. Participants also mentioned that more extensive discussion of legal aspects concerning advance directives should be included in paramedic training curricula. They suggested that palliative crisis cards should be integrated into end-of-life care. CONCLUSIONS: Decision making in prehospital end-of-life care is a challenge for all paramedics. The present investigation demonstrates that a dialogue bridging emergency medical and palliative care issues is necessary. The paramedics indicated that improved guidelines on end-of-life decisions and the termination of cardiopulmonary resuscitation in palliative care patients may be essential. Participants do not feel adequately trained in end-of-life care and the content of advance directives. Other recent studies have also demonstrated that there is a need for training curricula in end-of-life care for paramedics.

Bayesian models for multiple outcomes nested in domains.

We consider the problem of estimating the effect of exposure on multiple continuous outcomes, when the outcomes are measured on different scales and are nested within multiple outcome classes, or "domains." Our Bayesian model extends the linear mixed models approach to allow the exposure effect to differ across domains and across outcomes within domains. Our model can be parameterized to allow shrinkage of the effects within the different levels of nesting, or to allow fixed domain-specific effects with no shrinkage. Our model also allows covariate effects to differ across outcomes and domains. Our methodology is applied to data on prenatal methylmercury exposure and multiple outcomes in four domains measured at 9 years of age on children enrolled in the Seychelles Child Development Study. We use three different priors and found that our main conclusions were not sensitive to the choice of prior. Simulation studies examine the model performance under alternative scenarios. Our results demonstrate that a sizeable increase in power is possible.

Quality of out-of-hospital palliative emergency care depends on the expertise of the emergency medical team--a prospective multi-centre analysis.

BACKGROUND: The number of palliative care patients who live at home and have non-curable life-threatening diseases is increasing. This is largely a result of modern palliative care techniques (e.g. specialised out-of-hospital palliative medical care services), changes in healthcare policy and the availability of home care services. Accordingly, pre-hospital emergency physicians today are more likely to be involved in out-of-hospital emergency treatment of palliative care patients with advanced disease. METHODS: In a prospective multi-centre study, we analysed all palliative emergency care calls during a 24-month period across four emergency services in Germany. Participating pre-hospital emergency physicians were rated according to their expertise in emergency and palliative care as follows--group 1: pre-hospital emergency physicians with high experience in emergency and palliative medical care, group 2: pre-hospital emergency physicians with high experience in emergency medical care but less experience in palliative medical care and group 3: pre-hospital emergency physicians with low experience in palliative and emergency medical care. RESULTS: During the period of interest, the centres received 361 emergency calls requiring a response to palliative care patients (2.8% of all 12,996 emergency calls). Ten percent of all patients were treated by group 1; 42% were treated by group 2 and 47% were treated by group 3. There was a statistically significant difference in the treatment of palliative care patients (e.g. transfer to hospital, symptom control, end-of-life decision) as a result of the level of expertise of the investigated pre-hospital emergency physicians (p< 0.01). CONCLUSIONS: In Germany, out-of-hospital emergency medical treatment of palliative care patients depends on the expertise in palliative medical care of the pre-hospital emergency physicians who respond to the call. In our investigation, best out-of-hospital palliative medical care was given by pre-hospital emergency physicians who had significant expertise in palliative and emergency medical care. Our results suggest that it may be necessary to take the core principles of palliative care into consideration when conducting out-of-hospital emergency medical treatment of palliative care patients.

Modeling and Prediction of Multiple Correlated Functional Outcomes.

We propose a copula-based approach for analyzing functional data with correlated multiple functional outcomes exhibiting heterogeneous shape characteristics. To accommodate the possibly large number of parameters due to having several functional outcomes, parameter estimation is performed in two steps: first, the parameters for the marginal distributions are estimated using the skew t family, and then the dependence structure both within and across outcomes is estimated using a Gaussian copula. We develop an estimation algorithm for the dependence parameters based on the Karhunen-Loève expansion and an EM algorithm that significantly reduces the dimension of the problem and is computationally efficient. We also demonstrate prediction of an unknown outcome when the other outcomes are known. We apply our methodology to diffusion tensor imaging data for multiple sclerosis (MS) patients with three outcomes and identify differences in both the marginal distributions and the dependence structure between the MS and control groups. Our proposed methodology is quite general and can be applied to other functional data with multiple outcomes in biology and other fields.

Application of a novel suture anchor to abdominal wall closure.

BACKGROUND: Mesh suture used in high-tension wound closures produces large knots susceptible to increased palpability, infection, and foreign body response; yet has superior tensile strength and increased resistance to cutting through tissue compared to standard suture. This study investigates mesh suture fixation in abdominal tissue with a knotless novel, low-profile anchor-clip. METHODS: Single and double end fixation of mesh suture in swine rectus abdominus fascia with an anchor-clip, a knot, and predicate device fixation underwent cyclic testing followed by pull-to-failure testing. RESULTS: Failure load of standard knot, single corkscrew and double anchor-clip were not statistically different, but were significantly greater than single anchor-clip and double corkscrew fixation (p > 0.05). CONCLUSIONS: The anchor-clip is ∼60% smaller than a standard knot while maintaining fixation strength when exposed to physiologic forces using double anchor-clip fixation in abdominal wall closure.

Soft Tissue Anchoring Performance, Biomechanical Properties, and Tissue Reaction of a New Hernia Mesh Engineered to Address Hernia Occurrence and Recurrence.

One opportunity to reduce hernia occurrence and recurrence rates (currently estimated to be 30% at 10 years postoperatively) is by enhancing the ability of hernia meshes to anchor into tissue to prevent mesh migration, mesh contraction, and mesh tearing away from tissue. To address this, we developed a novel moderate-weight, macroporous, polypropylene mesh (termed the T-line mesh) with mesh extensions to optimize anchoring. We examined the physical properties, biomechanical performance, and biocompatibility of this novel mesh versus a predicate mesh anchored with #0-suture. The physical properties of the T-line mesh and predicate mesh were measured using American Society for Testing and Materials (ASTM) standards. Meshes were implanted into a swine hernia model and harvested after one day to determine anchoring strength of the meshes in the perioperative period. A separate group was implanted into a swine hernia model and harvested at 30 days and 90 days for semiquantitative histological analysis of biocompatibility. T-line mesh physical properties were similar to commonly used moderate-weight meshes in thickness and areal density. The T-line mesh outperformed the predicate mesh in all mechanical testing (P < 0.05). In the perioperative period, the T-line mesh was ∼275% stronger (P < 0.001) than the standard of care. Histological analysis of biocompatibility demonstrated no significant difference between the T-line mesh and predicate mesh (P > 0.05). The T-line mesh is a novel hernia mesh that outperforms a predicate mesh in mechanical and biomechanical performance testing while exhibiting similar biocompatibility. The T-line mesh has the potential to reduce hernia occurrence and recurrence caused by mechanical failure.

Aberrant crypt foci and semiparametric modeling of correlated binary data.

Motivated by the spatial modeling of aberrant crypt foci (ACF) in colon carcinogenesis, we consider binary data with probabilities modeled as the sum of a nonparametric mean plus a latent Gaussian spatial process that accounts for short-range dependencies. The mean is modeled in a general way using regression splines. The mean function can be viewed as a fixed effect and is estimated with a penalty for regularization. With the latent process viewed as another random effect, the model becomes a generalized linear mixed model. In our motivating data set and other applications, the sample size is too large to easily accommodate maximum likelihood or restricted maximum likelihood estimation (REML), so pairwise likelihood, a special case of composite likelihood, is used instead. We develop an asymptotic theory for models that are sufficiently general to be used in a wide variety of applications, including, but not limited to, the problem that motivated this work. The splines have penalty parameters that must converge to zero asymptotically: we derive theory for this along with a data-driven method for selecting the penalty parameter, a method that is shown in simulations to improve greatly upon standard devices, such as likelihood crossvalidation. Finally, we apply the methods to the data from our experiment ACF. We discover an unexpected location for peak formation of ACF.

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.

Local delivery of a zoledronate solution improves osseointegration of titanium implants in a rat distal femur model.

This study aimed to determine whether locally applied anti-resorptive agents acetazolamide or zoledronic acid would improve mechanical stability in implant osseointegration when applied as a solution within the medullary canal. Thirty-three rats received titanium-implants bilaterally in their intramedullary femoral canals. Prior to implantation, animals received 0.1 ml saline, 1 mM acetazolamide solution, or 0.7 mM zoledronic acid solution directly into the medullary cavity. The control group only received saline within the medullary canal while the treatment groups only received the respective treatment to which they were randomized. Animals were allowed to heal 4 weeks, at which time they were euthanized and femurs isolated for mechanical and radiographic evaluation. Push-out force to failure increased 152% in the zoledronic acid group relative to the control. There was no significant difference in push-out force with acetazolamide relative to control. Also, zoledronic acid increased metaphyseal bone volume fraction 46% and increased metaphyseal bone-implant contact 58% relative to the control. Recent research exploring local injection of medications to improve implant osseointegration and minimize systemic-effects has failed to quantitatively evaluate implant fixation strength on non-hydroxyapatite coated implants or implants without previous bone compaction. This study demonstrated that a simple injection of zoledronic acid into the medullary canal, rather than coatings or commercial gels, can increase fixation strength of an uncoated titanium-implant. Our findings indicate simple injection of zoledronic acid in saline solution has the potential for improving fixation of uncemented joint implants. Clinical Significance: Intramedullary injection of local bisphosphonate solutions could be implemented to improve osseointegration in cementless arthroplasty. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3294-3298, 2018.