Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Rabbit VX2 Liver Tumor Model: A Review of Clinical, Biology, Histology, and Tumor Microenvironment Characteristics.

The rabbit VX2 is a large animal model of cancer used for decades by interventional radiologists to demonstrate the efficacy of various locoregional treatments against liver tumors. What do we know about this tumor in the new era of targeted therapy and immune-oncology? The present paper describes the current knowledge on the clinics, biology, histopathology, and tumor microenvironment of VX2 based on a literature review of 741 publications in the liver and in other organs. It reveals the resemblance with human cancer (anatomy, vascularity, angiogenic profile, drug sensitivity, immune microenvironment), the differences (etiology, growth rate, histology), and the questions still poorly explored (serum and tissue biomarkers, genomic alterations, immune checkpoint inhibitors efficacy).

Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes.

BACKGROUND: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. METHODS: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18-35 years), middle (35-65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. RESULTS: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. CONCLUSIONS: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.

Novel characterization of the relationship between verbal list-learning outcomes and hippocampal subfields in healthy adults.

The relationship between hippocampal subfield volumetry and verbal list-learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list-learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle-aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list-learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association-based mnemonics mediated the relationship between verbal list-learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list-learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1.

Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students.

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18-26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

3D Segmentation of Perivascular Spaces on T1-Weighted 3 Tesla MR Images With a Convolutional Autoencoder and a U-Shaped Neural Network.

We implemented a deep learning (DL) algorithm for the 3-dimensional segmentation of perivascular spaces (PVSs) in deep white matter (DWM) and basal ganglia (BG). This algorithm is based on an autoencoder and a U-shaped network (U-net), and was trained and tested using T1-weighted magnetic resonance imaging (MRI) data from a large database of 1,832 healthy young adults. An important feature of this approach is the ability to learn from relatively sparse data, which gives the present algorithm a major advantage over other DL algorithms. Here, we trained the algorithm with 40 T1-weighted MRI datasets in which all "visible" PVSs were manually annotated by an experienced operator. After learning, performance was assessed using another set of 10 MRI scans from the same database in which PVSs were also traced by the same operator and were checked by consensus with another experienced operator. The Sorensen-Dice coefficients for PVS voxel detection in DWM (resp. BG) were 0.51 (resp. 0.66), and 0.64 (resp. 0.71) for PVS cluster detection (volume threshold of 0.5 within a range of 0 to 1). Dice values above 0.90 could be reached for detecting PVSs larger than 10 mm3 and 0.95 for PVSs larger than 15 mm3. We then applied the trained algorithm to the rest of the database (1,782 individuals). The individual PVS load provided by the algorithm showed a high agreement with a semi-quantitative visual rating done by an independent expert rater, both for DWM and for BG. Finally, we applied the trained algorithm to an age-matched sample from another MRI database acquired using a different scanner. We obtained a very similar distribution of PVS load, demonstrating the interoperability of this algorithm.

The MRi-Share database: brain imaging in a cross-sectional cohort of 1870 university students.

We report on MRi-Share, a multi-modal brain MRI database acquired in a unique sample of 1870 young healthy adults, aged 18-35 years, while undergoing university-level education. MRi-Share contains structural (T1 and FLAIR), diffusion (multispectral), susceptibility-weighted (SWI), and resting-state functional imaging modalities. Here, we described the contents of these different neuroimaging datasets and the processing pipelines used to derive brain phenotypes, as well as how quality control was assessed. In addition, we present preliminary results on associations of some of these brain image-derived phenotypes at the whole brain level with both age and sex, in the subsample of 1722 individuals aged less than 26 years. We demonstrate that the post-adolescence period is characterized by changes in both structural and microstructural brain phenotypes. Grey matter cortical thickness, surface area and volume were found to decrease with age, while white matter volume shows increase. Diffusivity, either radial or axial, was found to robustly decrease with age whereas fractional anisotropy only slightly increased. As for the neurite orientation dispersion and densities, both were found to increase with age. The isotropic volume fraction also showed a slight increase with age. These preliminary findings emphasize the complexity of changes in brain structure and function occurring in this critical period at the interface of late maturation and early ageing.

Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study.

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral (n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.

Efficacy evaluation of anin situforming tissue adhesive hydrogel as sealant for lung and vascular injury.

In situforming tissue adhesives based on biopolymers offer advantages over conventional sutures and staples in terms of biocompatibility, biodegradability, ease of application and improved patient compliance and comfort. Here, we describe the evaluation ofin situgelling hydrogel system based on dextran dialdehyde (DDA) obtained by periodate oxidization of dextran and chitosan hydrochloride (CH) as tissue adhesive. The hydrogel was prepared by reacting aldehyde functions in DDA with the amino functions in CH via Schiff's reaction. The gelation reaction was instantaneous and took just 4 s. The DDA-CH hydrogel as tissue adhesive was evaluated on a sheep lung parenchymal injury model and a pig aortic model and was compared with the commercially available tissue sealant, Bioglue®. The DDA-CH glue could completely seal the sheep lung incision site even at inflation with air way pressure of 30 cm of H2O with no air leak observed in the incision sites (n= 8) in any of the animals. Histological analyses showed mild inflammation after 2 weeks, comparable to Bioglue®. Resorption of test material by giant cells with no adverse effect on lung parenchyma was seen after 3 months. The DDA-CH glue was also very effective in sealing aortic incisions in a pig model (n= 4) with no failures and aneurisms. The endoluminal surface of the sealed incision in all cases showed intact apposition with adequate healing across the incision. No tissue necrosis or inflammation of endothelial surface could be seen grossly. Our studies show that the DDA-CH hydrogel could function as an effective sealant for the prevention of air and blood leaks following lung and vascular surgery.

The Perception of Plastic Surgery by Community-Based, Private Practice Nurses: A French National Descriptive Study.

Plastic surgery is a dynamic field but remains poorly understood by general practitioners, medical students, health professionals, and the public. The main health care professionals in the community who are involved in the follow-up of plastic surgery patients are nurses; they help to facilitate wound healing and rehabilitation in the postoperative period. In this study, the authors assessed the medical knowledge and perceptions of plastic surgery by nurses working in the community setting and explored their understanding of classical scenarios commonly encountered in reconstructive surgery. An online survey was designed to assess the demographics of nurses working in the community in France and their knowledge of plastic surgery. This was disseminated to all practicing nurses working outside of hospitals by means of an online social network from the period of April 2019 to June 2019. The survey was completed by 318 nurses. Specific training in plastic surgical nursing will be required to optimize the management of these patients following discharge from hospital. This gap in knowledge may affect patient recovery negatively.

Relationships between executive functioning and health-related quality of life in adult survivors of brain tumor and matched healthy controls.

INTRODUCTION: Few studies have considered health-related quality of life (HRQOL) as a primary outcome measure in adult survivors of primary brain tumor (PBT), and fewer still have studied the cognitive factors that may influence it. Research suggests that executive functions (EFs) are associated with HRQOL, but there is scant evidence to support this. The present study was conducted to (1) extend prior findings about HRQOL limitations in a sample of stable, long-term adult survivors of PBT, (2) investigate the associations between objective/reported EFs and HRQOL, and (3) identify the EFs that contribute most to HRQOL. METHOD: We recruited 40 survivors of PBT (> 2 years post-treatment) and 40 matched healthy controls. Participants completed an objective EF assessment (inhibition, working memory, shifting, and rule detection) and two self-report questionnaires probing EFs (Behavior Rating Inventory of Executive Function-Adult) and HRQOL (Medical Outcomes Study Short-Form 36). Participants' relatives completed observer-rated versions of these questionnaires. RESULTS: Patients' objective EF performances were relatively intact. However, patients and caregivers reported significantly more problems than healthy controls and their relatives, for both EFs and HRQOL. There were only negligible links between objective EFs and HRQOL, whereas numerous associations were found between reported EFs and HRQOL components. ANCOVA models revealed that specific reported EF processes contributed to both the physical and mental components of HRQOL, regardless of group. CONCLUSIONS: From a clinical point of view, this study demonstrates that even several years after end of treatment, adult PBT survivors experience substantial problems across different HRQOL domains. HRQOL assessment should therefore be part of the long-term follow-up of PBT survivors, and clinicians should consider EF limitations when designing appropriate survivorship care plans. These findings indicate that cognitive interventions targeting EFs could improve HRQOL.

Midterm Recanalization after Arterial Embolization Using Hydrogel-Coated Coils versus Fibered Coils in an Animal Model.

PURPOSE: To compare angiographic and pathologic effects (ie, occlusion, recanalization) after embolization with Hydrogel-coated coils (HydroCoils) and fibered coils in the renal and internal iliac arteries after 7 days and 1 and 4 months in an animal model. MATERIALS AND METHODS: Twelve sheep had 1 internal iliac and 1 renal artery randomly embolized with HydroCoils or fibered coils. Renal and internal iliac arteries were embolized with detachable 0.018-inch coils and pushable 0.035-inch coils, respectively. All animals had control angiography performed at 7 days, and 1 and 4 months to assess recanalization before euthanasia. Recanalization and inflammation were evaluated via pathologic examination. RESULTS: At 1 month, 100% of arteries embolized with HydroCoils were occluded vs 50% of those embolized with fibered coils (P = .004). At 4 months, 80% of arteries embolized with HydroCoils were occluded vs 25% of those embolized with fibered coils (P = .01). Surface of vessel occlusion was significantly greater for iliac arteries (96.7% ± 8.9) than for renal arteries (94.2% ± 5.3; P = .0076). Surface of occlusion of the renal arteries (92.2% ± 5.1) was lower for fibered coils than for HydroCoils (96.8% ± 4.7; P = .0287). Surface percentage of thrombus was significantly lower for HydroCoils than for fibered coils (P < .0001). Surface percentage of thrombus was correlated with surface percentage of recanalization (P = .0181). CONCLUSIONS: After 4 months, 75% of arteries embolized with fibered coils were recanalized vs 20% of those embolized with HydroCoils (P = .01). Reduced amount of thrombus after embolization with HydroCoils accounted for a reduced rate of arterial recanalization.

Lymphatic Transport and Lymph Node Location of Microspheres Subcutaneously Injected in the Vicinity of Tumors in a Rabbit Model of Breast Cancer.

PURPOSE: To assess the lymphatic transport of microparticles of 100 nm, 1 µm and 10 µm subcutaneously injected into the breast area of healthy and tumor-bearing rabbits, and to analyze their location in lymph node (LN) in relation to malignant cells. METHODS: Female rabbits (n = 9) bearing a VX2 tumor in one thoracic mammary gland were subcutaneously injected at D15 with polystyrene fluorescent particles around the nipple, on the tumor and on the healthy sides. The tumor and the LN measured by ultrasound at D9, D15 and D20 were explanted at D20. The LN metastases were evaluated by cytokeratin staining. LN uptake of the particles was measured by quantifying the green fluorescence surface in hot spot regions of healthy and pathologic LN. RESULTS: All animals developed mammary tumors. Metastases were found in 39% of LN from the tumor side. LN invasion was significantly lower for the 10 µm group versus the 100 nm group (p < 0.0348). The fully invaded area of metastatic LN contained significantly less 100 nm and 1 µm particles compared to the low and non-invaded regions and to the healthy LN. In the invaded LN, the 1 µm MS occupied more surface than the 100 nm particles. CONCLUSIONS: 1 µm MS arrived numerously into the areas low-invaded and non-invaded by the tumoral cells of the pathologic LN, but they were very rare in the fully invaded regions. Compared to the 100 nm nanospheres, the 1 µm were better retained (20 times) into the sentinel LN, showing the advantage of micrometric particles for lymph-targeted chemotherapy when injected before complete invasion by metastases.

Peripheral Embolization Using Hydrogel-Coated Coils Versus Fibered Coils: Short-Term Results in an Animal Model.

OBJECTIVES: To angiographically compare the occlusive effects of hydrocoils and fibered coils in the renal and internal iliac arteries at 24 h and 7 days in the sheep model. To determine the occlusive mechanism by hydrocoils and fibered coils by pathological examination. MATERIALS AND METHODS: Two types of peripheral hydrogel-coated and fibered coils similar in diameter and length were compared. The right and left renal arteries were embolized with 0.018-inch detachable hydrocoils or fibered coils in six sheep. Then, the right and left internal iliac arteries were embolized with 0.035-inch pushable hydrocoils or fibered coils. Arterial recanalization was evaluated at 24 h and at 7 days with angiography. At pathology, the surface percentage of thrombus and embolic material (platinum, Dacron fibers and hydrogel) and the presence of inflammation were assessed. RESULTS: No difference was found between the coils for recanalization at 24 h or 7 days. For hydrocoils, the surface of occlusion corresponded to thrombus for 42% and coil for 58% including 42% of platinum and 16% of hydrogel, respectively. For fibered coils, the surface of occlusion was composed of thrombus for 69% and of platinum and fibers for 31%. The surface percentage occupied by thrombus was significantly lower for hydrocoils than for fibered coils (p = 0.0047). The surface percentage of embolic was also different between the two products (p = 0.049). No degradation of hydrogel was found at any time points. CONCLUSION: The percentage of thrombus was significantly less with hydrocoils as compared to fibered coils, which may account for reduced long-term recanalization.

Predicting hemispheric dominance for language production in healthy individuals using support vector machine.

We used a Support Vector Machine (SVM) classifier to assess hemispheric pattern of language dominance of 47 individuals categorized as non-typical for language from their hemispheric functional laterality index (HFLI) measured on a sentence minus word-list production fMRI-BOLD contrast map. The SVM classifier was trained at discriminating between Dominant and Non-Dominant hemispheric language production activation pattern on a group of 250 participants previously identified as Typicals (HFLI strongly leftward). Then, SVM was applied to each hemispheric language activation pattern of 47 non-typical individuals. The results showed that at least one hemisphere (left or right) was found to be Dominant in every, except 3 individuals, indicating that the "dominant" type of functional organization is the most frequent in non-typicals. Specifically, left hemisphere dominance was predicted in all non-typical right-handers (RH) and in 57.4% of non-typical left-handers (LH). When both hemisphere classifications were jointly considered, four types of brain patterns were observed. The most often predicted pattern (51%) was left-dominant (Dominant left-hemisphere and Non-Dominant right-hemisphere), followed by right-dominant (23%, Dominant right-hemisphere and Non-Dominant left-hemisphere) and co-dominant (19%, 2 Dominant hemispheres) patterns. Co-non-dominant was rare (6%, 2 Non-Dominant hemispheres), but was normal variants of hemispheric specialization. In RH, only left-dominant (72%) and co-dominant patterns were detected, while for LH, all types were found, although with different occurrences. Among the 10 LH with a strong rightward HFLI, 8 had a right-dominant brain pattern. Whole-brain analysis of the right-dominant pattern group confirmed that it exhibited a functional organization strictly mirroring that of left-dominant pattern group. Hum Brain Mapp 38:5871-5889, 2017. © 2017 Wiley Periodicals, Inc.

Laparoscopic subperitoneal injection of chemo-loaded particles lowers tumor growth on a rabbit model of peritoneal carcinomatosis.

The purpose of our study was to assess the effect of controlled-release chemotherapy on the growth and viability of peritoneal carcinomatosis treated by subperitoneal injection in a rabbit VX2 model. A model of peritoneal carcinomatosis was created by laparoscopic injection of VX2 tumor in the left and right broad ligaments of 12 White New Zealand rabbits. At day 12, each tumor was randomly treated with a peritumoral injection of 0.5 mL microspheres loaded with doxorubicin (DEM-DOX) or unloaded (DEM-BLAND). Seven days after treatment, tumor volume, tumor viability in histology, local tumor necrosis in contact with DEM, and doxorubicin concentration profile around the drug eluting microspheres (DEM) were measured. Tumor volume was significantly lower in the DEM-DOX group (3.6 ± 3.2 cm3) compared with the DEM-BLAND group (8.9 ± 5.4 cm3) (p = 0.0425). The percentage of viable tumor tissue was significantly lower in the DEM-DOX group (38% ± 17%) compared with the DEM-BLAND group (56% ± 20%) (p = 0.0202). Tissue necrosis was observed around all DEM-DOX up to a distance of 1.094 ± 0.852 mm and never observed around DEM-BLAND. Drug concentration was above the therapeutic level of 1.0 µM up to a distance of 1.4 mm from the DEM to the tumor. Laparoscopic subperitoneal injection of chemo-loaded particles is feasible and lowers tumor growth and viability in a rabbit model of peritoneal carcinomatosis after 1 week.

[The new biomaterials of embolization: the shift to degradable]. / Les nouveaux biomatériaux de l'embolisation - La grande révolution du dégradable.

During the last decade, the interest of degradable embolics has considerably grown as alternatives for the currently-used permanent embolics: no permanent foreign body, recanalisation for repeat embolization, complete drug delivery in chemoembolization. Their design is not trivial since a lot of requirements need to be satisfied. The degradable embolics should be easily suspended in physiological solutions and contrast media, injectable in catheters with small internal lumen and they have to recover their size and shape after injection, as for any embolic. Moreover, they need to be loadable with various drugs, and their degradation has to be achieved in a given time before the onset of a chronic inflammatory response and vessel wall remodeling. Various approaches have been tested on diverse materials over the last years and have produced interesting results that make it possible to claim that the revolution of the degradable embolic has begun.

A novel injectable tissue adhesive based on oxidized dextran and chitosan.

A surgical adhesive that can be used in different surgical situations with or without sutures is a surgeons' dream and yet none has been able to fulfill many such demanding requirements. It was therefore a major challenge to develop an adhesive biomaterial that stops bleeding and bond tissues well, which at the same time is non-toxic, biocompatible and yet biodegradable, economically viable and appealing to the surgeon in terms of the simplicity of application in complex surgical situations. With this aim, we developed an in situ setting adhesive based on biopolymers such as chitosan and dextran. Dextran was oxidized using periodate to generate aldehyde functions on the biopolymer and then reacted with chitosan hydrochloride. Gelation occurred instantaneously upon mixing these components and the resulting gel showed good tissue adhesive properties with negligible cytotoxicity and minimal swelling in phosphate buffered saline (PBS). Rheology analysis confirmed the gelation process by demonstrating storage modulus having value higher than loss modulus. Adhesive strength was in the range 200-400gf/cm2 which is about 4-5 times more than that of fibrin glue at comparable setting times. The adhesive showed burst strength in the range of 400-410mm of Hg which should make the same suitable as a sealant for controlling bleeding in many surgical situations even at high blood pressure. Efficacy of the adhesive as a hemostat was demonstrated in a rabbit liver injury model. Histological features after two weeks were comparable to that of commercially available BioGlue®. The adhesive also demonstrated its efficacy as a drug delivery vehicle. The present adhesive could function without the many toxicity and biocompatibility issues associated with such products. STATEMENT OF SIGNIFICANCE: Though there are many tissue adhesives available in market, none are free of shortcomings. The newly developed surgical adhesive is a 2-component adhesive system based on time-tested, naturally occurring polysaccharides such as chitosan and dextran which are both biocompatible and biodegradable. Simple polymer modification has been carried out on both polysaccharides so that when aqueous solutions of both are mixed, the solutions gel in less than 10s and forms an adhesive that seals a variety of incisions. The strength of the adhesive is over 5-times the strength of commercially available Fibrin glue and is more tissue compliant than BioGlue®. This adhesive biomaterial showed excellent tissue bonding, was hemostatic, biocompatible and biodegradable. The significance of this work lies on the features of the developed tissue adhesive that it stops bleeding, bond the tissues well, can act as a drug delivery vehicle and would appeal to the surgeon in terms of the simplicity of application in complex surgical situations. There is no need for special delivery systems for application of this adhesive. The two-component adhesive can be applied one over the other using syringes. There is also no need for light curing with UV or visible light and the gelation between the two components spontaneously takes place on application leading to excellent tissue bonding.

Dynamic prediction models for clustered and interval-censored outcomes: Investigating the intra-couple correlation in the risk of dementia.

The use of settings such as cohorts or clinical trials with interval-censored data and clustered event times are increasingly popular designs. First, the observed outcomes cannot be considered as independent and random effects survival models were introduced. Second, the failure time is not known exactly but it is only known to have occurred within a certain interval. We propose here an extension of shared frailty models to handle simultaneously the interval censoring, the clustering and also left truncation due to delayed entry in the cohort. A simulation study to evaluate the proposed method was conducted. The estimated results are used to obtain dynamic predictions for clustered patients, with interval-censored failure times and with a given history. We apply our method to the Three-City study, a prospective cohort with periodic follow-up in order to study prognostic factors of dementia. In this application scheme, couples are natural clusters and an intra-couple correlation might be present with a possible increased risk for dementia for subjects whose partner already developed incident dementia. No significant intra-couple correlation for the risk of dementia was observed before and after adjustments for covariates. We also present individual predictions of dementia underlining the usefulness of dynamic prognostic tools that can take into account the clustering. The consideration of frailty models for interval-censoring data and left-truncated data permits useful analysis of very complex clustered data. It could help to improve estimation of the impact of proposed prognostic features in a study with clustering. We proposed here a tractable model and a dynamic prediction tool that can easily be implemented using the R package Frailtypack.