First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria.

BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism. METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 µg (n = 9) or 50 µg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

Physical versus psychosocial stress: effects on hormonal, autonomic, and psychological parameters in healthy young men.

As a time-efficient training system, high intensity interval training (HIIT) is well known for several beneficial effects. However, the literature on the stress-generating effects of HIIT shows a research deficit. A standardized comparable stressor and different kinds of stress-parameters are needed for quantifying the results. The present study examined the hormonal, autonomic, and psychological stress outcomes of HIIT compared to a standardized psychosocial stressor and tested the cross-stressor-adaptation (CSA) hypothesis which implies a stress-buffering effect at a good fitness level. In a sample of 32 healthy young males (24.31 ± 3.35 years of age) stress was induced with a multiple Wingate (WG), as a HIIT all-out performance test, involving four 30 sec all-out exercise bouts. In addition, the Trier Social Stress Test (TSST), which consists of a mock job interview and mental arithmetic performance, was used for stress induction. Cortisol, heart rate variability (HRV), and stress-related questionnaires were assessed before, during, and after stress induction. Both the Wingate as well as the TSST led to a highly significant change in time and stressor for cortisol and HRV. Furthermore, a significantly higher delta during Wingate was identified. In part, the TSST had a significantly higher impact on the psychological measurements than the WG. In contrast to the literature, this study was not able to confirm the stress-buffering effect of the CSA hypothesis. These findings prove the stressful effect of HIIT. The prevention of negative health effects needs to be taken into consideration in sports training methods and programs as well as in stress-related research Lay summary By using a well-estimated psychosocial stressor for comparison and several stress parameters, this study is able to show the strong stress-generating effect of high intensity interval training (HIIT). Interestingly, subjective stress perception differed from objective stress response. This research is an important step towards understanding stress-related disorders in elite sport and making recommendations for reducing autonomic as well as hormonal stress in high intensity sport.

Nerve size correlates with clinical severity in Charcot-Marie-Tooth disease 1A.

INTRODUCTION: Nerve cross-sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A. METHODS: We assessed 56 patients with CMT1A (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar, and fibular nerves. RESULTS: Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed that ulnar motor nerve conduction velocity (ß: -0.19) and fibular compound muscle action potential amplitude (-1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (ß: 5.29) and CMTES2 (4.28). DISCUSSION: Nerve size is significantly associated with clinical scores in CMT1A, which suggests that it might represent a potential biomarker of CMT damage and progression.

Effect of "phase change" complex on postoperative adhesion prevention.

BACKGROUND: Postsurgical peritoneal adhesion is a major clinical problem. Numerous anti-adhesion products have been studied, but none could be easily used to provide a physical barrier. In this study, we developed a "phase change" anti-adhesion barrier for reducing peritoneal adhesion by cross-linked copolymerization of O-carboxymethyl chitosan (CMC) and CaCl2 and addition of cyclosporin A (CsA). MATERIALS AND METHODS: The CMC-CaCl2-CsA compound was characterized by equilibrium swelling rate, weight loss, releasing effect, and coagulation test, and its biosafety was characterized by acute oral toxicity, hemolysis, and cytotoxicity. Intestinal adhesion model was applied on 64 Sprague-Dawley rats, which received CMC, CMC-CaCl2, or CMC-CaCl2-CsA treatment. At postoperative days 7 and 14, the rats were euthanized, and adhesions were graded by an investigator blinded to the treatment groups, using a predetermined adhesion scoring system. The cecum and adhesion tissue were stained with hematoxylin and eosin and antibodies for matrix metalloproteinase-9 and TIMP-1 for further histopathologic examination. RESULTS: The phase change anti-adhesive material exhibited effective blood clotting and were nontoxic in clotting experiments and acute toxicity test. The degradation rate could be adjusted using phosphate-buffered solution with varying pH. Adhesions were significantly reduced in the CMC-CaCl2-CsA treatment group compared with the control group (P < 0.001). Expression of matrix metalloproteinase-9 was stronger in CMC-CaCl2-CsA treatment group at 7 days after surgery. CONCLUSIONS: "Phase-change" adhesive can undergo changes after application, and it inhibits the formation of abdominal adhesions after surgery. The material is convenient for using by surgeons and provides an effective tool for intestinal adhesion prevention.

Specific collagen peptides increase adaptions of patellar tendon morphology following 14-weeks of high-load resistance training: A randomized-controlled trial.

ABSTRACTThe purpose of this study was to investigate the effect of a supplementation with specific collagen peptides (SCP) combined with resistance training (RT) on changes in structural properties of the patellar tendon. Furthermore, tendon stiffness as well as maximal voluntary knee extension strength and cross-sectional area (CSA) of the rectus femoris muscle were assessed. In a randomized, placebo-controlled study, 50 healthy, moderately active male participants completed a 14-week resistance training program with three weekly sessions (70-85% of 1 repetition maximum [1RM]) for the knee extensors. While the SCP group received 5g of specific collagen peptides daily, the other group received the same amount of a placebo (PLA) supplement. The SCP supplementation led to a significant greater (p < 0.05) increase in patellar tendon CSA compared with the PLA group at 60% and 70% of the patellar tendon length starting from the proximal insertion. Both groups increased tendon stiffness (p < 0.01), muscle CSA (p < 0.05) and muscular strength (p < 0.001) throughout the intervention without significant differences between the groups. The current study shows that in healthy, moderately active men, supplementation of SCP in combination with RT leads to greater increase in patellar tendon CSA than RT alone. Since underlying mechanisms of tendon hypertrophy are currently unknown, further studies should investigate potential mechanisms causing the increased morphology adaptions following SCP supplementation.Trial registration: German Clinical Trials Register identifier: DRKS00029244..

A daily supplementation of 5 g of specific collagen peptides during 14 weeks of high-load resistance training increase patellar tendon hypertrophy compared to the same training regimen and placebo.The resistance training-induced CSA increase, which was most pronounced on proximal and medial patellar tendon sites, is uniformly potentiated along the entire tendon length by supplementation.Patellar tendon stiffness, CSA of the rectus femoris muscle and maximal voluntary knee extension strength increase due to training independently from supplementation.Increased tendon CSA as a result of a stimulating effect of the supplementation with specific collagen peptides on collagen synthesis might be able to decrease tendon stress and support tendon healing.

Ceragenin CSA-44 as a Means to Control the Formation of the Biofilm on the Surface of Tooth and Composite Fillings.

Recurrent oral infections, as manifested by endodontic and periodontal disease, are often caused by Enterococcus faecalis (E. faecalis) and Candida albicans (C. albicans). Here, we assessed the anti-biofilm activity of ceragenin CSA-44 against these microbes growing as a biofilm in the presence of saliva on the surface of human teeth and dental composite (composite filling) subjected to mechanical stresses. Methods: Biofilm mass analysis was performed using crystal violet (CV) staining. The morphology, viscoelastic properties of the biofilm after CSA-44 treatment, and changes in the surface of the composite in response to biofilm presence were determined by AFM microscopy. Results: CSA-44 prevented biofilm formation and reduced the mass of biofilm formed by tested microorganisms on teeth and dental composite. Conclusion: The ability of CSA-44 to prevent the formation and to reduce the presence of established biofilm on tooth and composite filling suggests that it can serve as an agent in the development of new methods of combating oral pathogens and reduce the severity of oral infections.

Improvement and analysis of mechanistic modeling of root canal preparation by a computer-based method.

BACKGROUND AND OBJECTIVE: Root canal preparation is a cutting process between nickel-titanium (Ni-Ti) file and root canal, which aims to remove the bacteria and to keep teeth from infection. A mechanistic model in root canal preparation is proposed to investigate the mechanical mechanism of Ni-Ti file, which is essential to prevent physical and thermal damage on root canal. METHODS: First, the mathematic modeling is introduced based on oblique cutting theory, which the loading condition of Ni-Ti file is derived from each cutting element by expressing a function of geometric parameters. For the modeling improvement, a cutting simulation algorithm (CSA) based on Boolean operation is proposed to achieve the complicated cutting situation between root canal and Ni-Ti file instantaneously. After establishment of model, the predictive precision is verified by conducting in vitro experiments. Eighteen artificial root canals were prepared in 6 mm straight and 2 mm C-shaped curved specification with 0.3 mm diameter, which was a single canal for each position, all the canals do not have connections with each other. During experiments, root canals were prepared using Wave One Gold (GWO) instruments with reciprocating rotational motion. Different influential factors (curvatures of root canal and movements of Ni-Ti file) and cutting parameters (feed rate and spindle speed) were analyzed by conducting a series of simulations under the mechanistic model. RESULTS: Experiment results show that the predictive error of thrust force based on the proposal model is around 15%. The thrust force will increase dramatically after Ni-Ti file gets into craved canal. It can be indicated that the curvatures of root canal, movements of Ni-Ti file have a strong influence on root canal preparation. 20° increasement of curved degrees can lead to the 0.73 N increase of thrust force, while pecking movement can decrease 19.88% of thrust force compared with continues one. Furthermore, investigation on pecking distance represent that 2-1 mm movement can effectively reduce the thrust force of 15.82% compared to 4-2 mm movement. CONCLUSION: Based on simulation results, 2-1 mm pecking movement is recommended for dentists compared with 4-2 mm pecking movement or continues movement. In addition, this paper provides a novel insight of interactive mechanism between Ni-Ti file and root canal, so as to contribute to both the theoretical and practical research by elucidating mechanisms and providing quantitative predictions that can be validated. Compared with conventional analytical model, both calculated precision and efficiency are improved in the proposed model.

Immunofluorescence studies to dissect the impact of Cockayne syndrome A alterations on the protein interaction and cellular localization.

BACKGROUND: Cockayne syndrome (CS), which was discovered by Alfred Cockayne nearly 75 years ago, is a rare autosomal recessive disorder characterized by growth failure, neurological dysfunction, premature aging, and other clinical features including microcephaly, ophthalmologic abnormalities, dental caries, and cutaneous photosensitivity. These alterations are caused by mutations in the CSA or CSB genes, both of which are involved in transcription-coupled nucleotide excision repair (TC-NER), the sub-pathway of NER that rapidly removes UV-induced DNA lesions which block the progression of the transcription machinery in the transcribed strand of active genes. Several studies assumed that CSA and CSB genes can play additional roles outside TC-NER, due to the wide variations in type and severity of the CS phenotype and the lack of a clear relationship between genotype and phenotype. To address this issue, our lab generated isogenic cell lines expressing wild type as well as different versions of mutated CSA proteins, fused at the C-terminus with the Flag and HA epitope tags (CSAFlag-HA). In unpublished data, the identity of the CSA-interacting proteins was determined by mass spectrometry. Among which three subunits (namely, CCT3, CCT8, and TCP1) of the TRiC/CCT complex appeared as novel interactors. TRiC is a chaperonin involved in the folding of newly synthesized or unfolded proteins. The aim of this study is directed to investigate by immunofluorescence analysis the impact of the selected CSA mutations on the subcellular localization of the CSA protein itself as well as on its novel interactors CCT3, CCT8, and TCP1. RESULTS: We showed that specific CSA mutations impair the proper cellular localization of the protein, but have no impact on the cellular distribution of the TRiC subunits or CSA/TRiC co-localization. CONCLUSION: We suggested that the activity of the TRiC complex does not rely on the functionality of CSA.

Inflammatory and fibroblastic effects of azithromycin on cyclosporine-induced gingival overgrowth in renal transplanted patients with and without scaling: A randomized clinical trial.

BACKGROUND: This study aimed to evaluate the effect of azithromycin (AZM) on the inflammatory and fibroblastic part of cyclosporine A (CsA)-induced gingival overgrowth (GO) in renal transplanted patients. METHODS: In this randomized clinical trial, subjects with GO receiving CsA were randomly divided into two groups: those receiving 5-day AZM only (n = 12; group 1) and those receiving scaling and prescribed AZM after 2 months (n = 12; group 2). Both groups were evaluated for several indices (gingival hyperplastic index, plaque and bleeding index, clinical crown length) at the first visit and the 4th and 8th week in group 1, and at the first visit and the 4th, 8th, 12th, and 16th week in group 2. RESULTS: The sample included 24 individuals. The mean (SD) age of participants was 30.81 (11.13) and 34.80 (9.33) years in group 1 and 2, respectively. Based on ANCOVA, the changes in the hyperplastic index (GHI) and apico-coronal dimension (ACD) of it were statistically significant in professional scaling accompanied by AZM group (P = 0.012 and 0.031, respectively). However, no significant change was observed in mean indices after prescribing AZM in 5-day AZM regimen group (P = 0.664 and 0.882, respectively). According to one-way ANOVA, we found a statistically significant correlation in GHI, ACD, bleeding index (BI), and plaque index (PI) accounting for P = 0.012, 0.003, 0.002, and <0.001, respectively. CONCLUSIONS: Findings suggest that AZM cannot influence the fibroblastic part of GO in presence of gum inflammation while the therapy can improve GO after resolving it with scaling.

Evaluation of inductive effects of different concentrations of cyclosporine A on MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 in fetal and adult human gingival fibroblasts.

Background The etiology of gingival overgrowth due to cyclosporine A (CsA) is still unknown. The aim of this study was to determine the possible role of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) on extra-cellular matrix (ECM) homeostasis when treated with different levels of CsA and its difference between fetal and adult human gingival fibroblasts (HGFs). Methods Each group of cells (adult and fetal) was cultured in 40 wells that consisted of four different CsA treatment concentrations. Every 10 wells were treated with 0, 50, 100, and 150 ng/mL of CsA which makes a total of 80 wells. Supernatants of every well were used to determine the concentration of MMPs and TIMPs using the Elisa kits from Boster, CA, USA. Results MMP-1 level increased with the treatment of CsA when treated with 50 and 150 ng/mL of CsA (p = 0.02 and p = 0.04) as TIMP-1 decreased (p < 0.0001) in adult group; while in the fetal group, TIMP-1 level increased with treatment of 150 ng/mL (p < 0.0001). MMP-2 level increased in both adult and fetal groups (p < 0.0001). MMP-3 level decreased in adult group (p < 0.0001) but went up in fetal HGFs (p = 0.01) when treated with 150 ng/mL CsA. TIMP-2 level increased in all wells significantly when treated with CsA (p < 0.0001). The study showed that CsA affects secretion of MMPs and TIMPs. MMP-1 increment and TIMP-1 decrement were observed, which indicate more degradation of ECM. This may be due to single donor use in this study. TIMP-2 and MMP-2 were both more active when treated with CsA which may be due to the gelatinase activity of them and that in CsA gingival overgrowth. There was more inflammation rather than fibrosis.

Influence of Age and Tooth Loss on Masticatory Muscles Characteristics: A Population Based MR Imaging Study.

BACKGROUND: Aging is associated with a decline in masticatory muscles mass and performance. The present study aims to examine the differences in the cross-sectional areas of the masseter, medial and lateral pterygoid muscles in relation to age and the present dental status in a population-based magnetic resonance imaging study. METHODS: This cross sectional study involved 747 subjects aged between 30-89 years (344 male, 403 female) who underwent both a whole body MRI and a full oral examination. The cross-sectional areas of the masseter, medial and lateral pterygoid muscles were measured from MRI images using the software Osirix. Dental and prosthetic status data from the oral examination were classified according to Eichner index. The method of generalized least squares, also called growth curve model, was used to examine the associations between the cross-sectional areas, age and tooth status. RESULTS: The cross-sectional area of the lateral pterygoid muscle decreased substantially with age in women but did not depend on age in men. The medial pterygoid muscle depended on age but an effect modification by gender was uncertain. Masseter muscle was weakly associated with age but strongly associated with the number of teeth in both genders. CONCLUSIONS: Our findings suggest that age has a heterogeneous effect on masticatory muscles. This indicates that age related changes to the masticatory muscles are muscle specific and are not consistent between the different muscles.

Stability, safety, and transcorneal mechanistic studies of ophthalmic lyophilized cyclosporine-loaded polymeric micelles.

INTRODUCTION: Cyclosporine-A (CsA) is generally used as an immunosuppressant and is also prescribed for some ophthalmic applications such as vernal keratoconjunctivitis and dry eye. However, it is limited clinically due to its low aqueous solubility and ocular bioavailability. METHODS: In this work, lyophilized methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) polymer micelles were prepared for ophthalmic formulations as a promising nanocarrier for hydrophobic drugs like CsA. A mPEG-PLA diblock polymer was synthesized by ring opening polymerization and CsA was loaded into mPEG-PLA micelles by a simple film dispersion method. A uniform design of experiments was utilized to optimize the final formulation. The obtained formulation was characterized for diameter (57.0±3.2 nm), entrapment efficiency % (98.51±1.4), and in vitro release. Moreover, incorporating the stabilizer mPEG2000 could increase the in vitro stability of the lyophilized CsA-loaded mPEG-PLA micelles. RESULTS: Results showed a sustained release of CsA from the micelles. Drug concentration and time-dependent cytotoxicity of human corneal epithelial-2 cells was observed. Additionally, the transcorneal mechanism of mPEG-PLA micelles was studied and the results showed that the mPEG-PLA micelles mainly absorbed by a paracellular pathway via corneal epithelial cells. CONCLUSION: Taken together, the results proved that this mPEG-PLA diblock polymer can be potentially used as a nanoscopic carrier to deliver hydrophobic drugs in a controlled manner to the ocular region and, thus, deserves further attention.

Nerve ultrasound findings differentiate Charcot-Marie-Tooth disease (CMT) 1A from other demyelinating CMTs.

OBJECTIVE: Ulnar/median motor nerve conduction velocity (MNCV) is ≤38 m/s in demyelinating Charcot-Marie-Tooth disease (CMT). Previous nerve high resolution ultrasound (HRUS) studies explored demyelinating CMT assuming it as a homogeneous genetic/pathological entity or focused on CMT1A. METHODS: To explore the spectrum of nerve HRUS findings in demyelinating CMTs, we recruited patients with CMT1A (N = 44), CMT1B (N = 9), CMTX (N = 8) and CMT4C (N = 4). They underwent nerve conduction study (NCS) and HRUS of the median, ulnar, peroneal nerve, and the brachial plexus. RESULTS: Median, ulnar and peroneal MNCV significantly differed across CMT subtypes. Cross sectional area (CSA) was markedly and diffusely enlarged at all sites, except entrapment ones, in CMT1A, while it was slightly enlarged or within normal range in the other CMTs. No significant right-to-left difference was found. Age had limited effect on CSA. CSAs of some CMT1A patients largely overlapped with those of other demyelinating CMTs. A combination of three median CSA measures could separate CMT1A from other demyelinating CMTs. CONCLUSIONS: Nerve HRUS findings are heterogeneous in demyelinating CMTs. SIGNIFICANCE: Nerve HRUS may separate CMT1A from other demyelinating CMTs. The large demyelinating CMTs HRUS spectrum may be related to its pathophysiological variability.

Er:YAG Laser and Cyclosporin A Effect on Cell Cycle Regulation of Human Gingival Fibroblast Cells.

Introduction: Periodontitis is a set of inflammatory disorders characterized by periodontal attachment loss and alveolar bone resorption. Because of deficiency in periodontitis mechanical therapy, this study was aimed to explore the molecular influence of the erbiumdoped: yttrium aluminum garnet (Er:YAG) laser and cyclosporin A (CsA) on human gingival fibroblasts (HGFs) for improvement in periodontal diseases therapy. Methods: We focused on articles that studied the proteome profiles of HGFs after treatment with laser irradiation and application of CsA. The topological features of differentially expressed proteins were analyzed using Cytoscape Version 3.4.0 followed by module selection from the protein-protein interaction (PPI) network using Cluster ONE plugin. In addition, we performed gene ontology (GO) enrichment analysis for the densely connected region and key proteins in both PPI networks. Results: Analysis of PPI network of Er:YAG laser irradiation on HGFs lead to introducing YWHAZ, VCP, HNRNPU, YWHAE, UBA52, CLTC, FUS and IGHG1 as key proteins while similar analysis revealed that ACAT1, CTSD, ALDOA, ANXA2, PRDX1, LGALS3, ARHGDI and EEF1A1 are the crucial proteins related to the effect of drug. GO enrichment analysis of hubbottleneck proteins of the 2 networks showed the different significant biological processes and cellular components. The functional enrichments of module of Er:YAG laser network are included as fatty acid transmembrane transport, cytokinesis, regulation of RNA splicing and asymmetric protein localization. There are not any significant clusters in network of HGF treated by CsA. Conclusion: The results indicate that there are 2 separate biomarker panels for the 2 treatment methods.

Development of a novel CsA-PLGA drug delivery system based on a glaucoma drainage device for the prevention of postoperative fibrosis.

The formation of a scar after glaucoma surgery often leads to unsuccessful control of intraocular pressure, and should be prevented by using a variety of methods. We designed and developed a novel drug delivery system (DDS) comprising cyclosporine A (CsA) and poly(lactic-co-glycolic acid) (PLGA) based on a glaucoma drainage device (GDD) that can continuously release CsA to prevent postoperative fibrosis following glaucoma surgery. The CsA@PLGA@GDD DDS was observed by field emission scanning electron microscopy and revealed an asymmetric pore structure. Thermogravimetric analysis was performed to measure the weight loss and evaluate the thermal stability of the CsA@PLGA@GDD DDS. The in vitro drug release profile of the DDS was studied using high performance liquid chromatography, which confirmed that the DDS released CsA at a stable rate and maintained adequate CsA concentrations for a relatively long time. The biocompatibility of the DDS and the inhibitory effects on the postoperative fibrosis were investigated in vitro using rabbit Tenon's fibroblasts. The in vivo safety and efficacy of the DDS were examined by implanting the DDS into Tenon's capsules in New Zealand rabbits. Bleb morphology, intraocular pressure, anterior chamber reactions, and anterior chamber angiography were studied at a series of set times. The DDS kept the filtration pathway unblocked for a longer time compared with the control GDD. The results indicate that the CsA@PLGA@GDD DDS represents a safe and effective strategy for preventing scar formation after glaucoma surgery.

From bench-top to chair-side: how scientific evidence is incorporated into clinical practice.

OBJECTIVES: The objective of this manuscript is to describe the process through which bench-top research is incorporated into clinical practice from an evidence-based dentistry perspective. METHODS: Relevant literature is reviewed to describe the translation of bench-top research to clinical practice through the steps of preclinical testing; human clinical trials; systematic review development (question development, search/screen methods, evidence synthesis, and evidence appraisal); clinical recommendation development; dissemination strategies; the role of the clinician in finding and appraising relevant evidence; barriers to implementation with strategies to overcome those barriers; and finally, the fusion of evidence with clinician experience and patient needs and preferences in clinical decision-making. SIGNIFICANCE: Descriptions of processes, methodologies, tools, and resources are provided to help researchers and clinicians alike understand the steps that lie between bench-top research and clinical implementation. With mutual understanding of the complexity involved in translating research into practice, it is hoped that barriers to implementation can be overcome that should lead to improved patient health outcomes.

Characterization of a novel active release coating to prevent biofilm implant-related infections.

Biofilm implant-related infections cost the US healthcare system billions of dollars each year. For several decades, device coatings have been developed that actively release antimicrobial compounds in an attempt to prevent these infections from developing. To date, few coatings have been put into clinical use. These have shown limited to no efficacy in clinical trials. Recent data have shown the in vitro and in vivo efficacy of a novel active release coating that may address the limitations of coatings that are used clinically. In this study, the novel active release coating was characterized to gain an understanding of the effects of combining an antimicrobial additive, cationic steroid antimicrobial-13 (CSA-13), to a medical grade polydimethylsiloxane (PDMS) material. Results indicated that the addition of CSA-13 did influence the physical properties of the PDMS, but not with adverse effects to the desired material properties. Furthermore, there was no indication of chemical reactivity. It was shown that CSA-13 was uniformly dispersed as small particles throughout the PDMS matrix. These particles were able to dissolve and elute out of the PDMS within a 30-day period. The results of this work suggested that the PDMS with CSA-13 was thermally, chemically and physically stable when used as a device coating to treat local infection and/or prevent biofilm implant-related infections from developing.

Supersaturated polymeric micelles for oral cyclosporine A delivery.

Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81-3.53 (p < 0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6 ± 24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption.