Using health-related quality of life instruments for children with long-term conditions : On the basis of a national quality registry system

Introduction: There has been a continuous development of new technologies in healthcare that are derived from national quality registries. However, this innovation needs to be translated into the workflow of healthcare delivery, to enable children with long-term conditions to get the best support possible to manage their health during everyday life. Since children living with long-term conditions experience different interference levels in their lives, healthcare professionals need to assess the impact of care on children’s day-to-day lives, as a complement to biomedical assessments. Aim: The overall aim of this thesis was to explore and describe the use of instruments about health-related quality of life (HRQOL) in outpatient care for children with long-term conditions on the basis of a national quality registry system. Methods: The research was conducted by using comparative, cross-sectional and explorative designs and data collection was performed by using different methods. The questionnaire DISABKIDS Chronic Generic Measure -37 was used as well as semi-structured interviews and video-recordings from consultations. Altogether, 156 children (8–18 years) and nine healthcare professionals participated in the studies. Children with Type 1 Diabetes (T1D) (n 131) answered the questionnaire DISABKIDS and children with rheumatic diseases, kidney diseases and T1D (n 25) were interviewed after their consultation at the outpatient clinic after the web-DISABKIDS had been used. In total, nine healthcare professionals used the HRQOL instrument as an assessment tool during the encounters which was video-recorded (n 21). Quantitative deductive content analysis was used to describe content in different HRQOL instruments. Statistical inference was used to analyse results from DISABKIDS and qualitative content analysis was used to analyse the interviews and video-recordings. Results: The findings showed that based on a biopsychosocial perspective, both generic and disease-specific instruments should be used to gain a comprehensive evaluation of the child’s HRQOL. The DISABKIDS instrument is applicable when describing different aspects of health concerning children with T1D. When DISABKIDS was used in the encounters, children expressed positive experiences about sharing their results with the healthcare professional. It was discovered that different approaches led to different outcomes for the child when the healthcare professionals were using DISABKIDS during the encounter. When an instructing approach is used, the child’s ability to learn more about their health and how to improve their health is limited. When an inviting or engaging approach is used by the professional, the child may become more involved during the conversations. Conclusions: It could be argued that instruments of HRQOL could be used as a complement to biomedical variables, to promote a biopsychosocial perspective on the child’s health. According to the children in this thesis, feedback on their results after answering to web-DISABKIDS is important, which implies that healthcare professionals need to prioritize time for discussions about results from HRQOL instruments in the encounters. If healthcare professionals involve the child in the discussion of the results of the HRQOL, misinterpreted answers could be corrected during the conversation. Concurrently, this claims that healthcare professionals invite and engage the child.

Targeting microRNAs involved in the BDNF signaling impairment in neurodegenerative diseases

Neurodegenerative diseases are becoming an ever-increasing problem in aging populations. Low levels of brain-derived neurotrophic factor (BDNF) have previously been associated with the pathogenesis of numerous neurodegenerative diseases. Recently, microRNAs (miRNAs) have been proposed as potential novel therapeutic targets for treating various diseases of the central nervous system (CNS), and interestingly, few studies have reported several miRNAs that downregulate the expression levels of BDNF. However, substantial challenges exist when attempting to translate these findings into practical anti-miRNA therapeutics, especially when the targets remain inside the CNS. Thus, in this review, we summarize the specific molecular mechanisms by which several miRNAs negatively modulate the expressions of BDNF, address the potential clinical difficulties that can be faced during the development of anti-miRNA-based therapeutics and propose strategies to overcome these challenges.

Infection of the central nervous system by Mycobacterium tuberculosis in patients infected with human immunodeficiency virus (the new neurotuberculosis)

Neurologic complications of HIV infection are numerous. This review focuses on the clinical presentation, diagnostic particularities and therapeutic issues of neurotuberculosis. The pertinent literature describing this important infection is succinctly summarized with a particular emphasis on the discussion of differences in clinical presentation between HIV-infected and -uninfected patients.

Production Diseases in European Organic Dairy Farms – Current Status and Identification of Drivers for Improvement by Means of a Systemic Approach

The aims of this thesis were to determine the animal health status in organic dairy farms in Europe and to identify drivers for improving the current situation by means of a systemic approach. Prevalences of production diseases were determined in 192 herds in Germany, France, Spain, and Sweden (Paper I), and stakeholder consultations were performed to investigate potential drivers to improve animal health on the sector level (ibid.). Interactions between farm variables were assessed through impact analysis and evaluated to identify general system behaviour and classify components according to their outgoing and incoming impacts (Paper II-III). The mean values and variances of prevalences indicate that the common rules of organic dairy farming in Europe do not result in consistently low levels of production diseases. Stakeholders deemed it necessary to improve the current status and were generally in favour of establishing thresholds for the prevalence of production diseases in organic dairy herds as well as taking actions to improve farms below that threshold. In order to close the gap between the organic principle of health and the organic farming practice, there is the need to formulate a common objective of good animal health and to install instruments to ensure and prove that the aim is followed by all dairy farmers in Europe who sell their products under the organic label. Regular monitoring and evaluation of herd health performance based on reference values are considered preconditions for identifying farms not reaching the target and thus in need of improvement. Graph-based impact analysis was shown to be a suitable method for modeling and evaluating the manifold interactions between farm factors and for identifying the most influential components on the farm level taking into account direct and indirect impacts as well as impact strengths. Variables likely to affect the system as a whole, and the prevalence of production diseases in particular, varied largely between farms despite some general tendencies. This finding reflects the diversity of farm systems and underlines the importance of applying systemic approaches in health management. Reducing the complexity of farm systems and indicating farm-specific drivers, i.e. areas in a farm, where changes will have a large impact, the presented approach has the potential to complement and enrich current advisory practice and to support farmers’ decision-making in terms of animal health.

Interspecies study of the enteric nervous system and related pathologies

The enteric nervous system (ENS) modulates a number of digestive functions including well known ones, i.e. motility, secretion, absorption and blood flow, along with other critically relevant processes, i.e. immune responses of the gastrointestinal (GI) tract, gut microbiota and epithelial barrier . The characterization of the anatomical aspects of the ENS in large mammals and the identification of differences and similarities existing between species may represent a fundamental basis to decipher several digestive GI diseases in humans and animals. In this perspective, the aim of the present thesis is to highlight the ENS anatomical basis and pathological aspects in different mammalian species, such as horses, dogs and humans. Firstly, I designed two anatomical studies in horses:  “Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter”.  “Localization of 5-hydroxytryptamine 4 receptor (5-HT4R) in the equine enteric nervous system”. Then I focused on the enteric dysfunctions, including:  A primary enteric aganglionosis in horses: “Extrinsic innervation of the ileum and pelvic flexure of foals with ileocolonic aganglionosis”.  A diabetic enteric neuropathy in dogs: “Quantification of nitrergic neurons in the myenteric plexus of gastric antrum and ileum of healthy and diabetic dogs”.  An enteric neuropathy in human neurological patients: “Functional and neurochemical abnormalities in patients with Parkinson's disease and chronic constipation”. The physiology of the GI tract is characterized by a high complexity and it is mainly dependent on the control of the intrinsic nervous system. ENS is critical to preserve body homeostasis as reflect by its derangement occurring in pathological conditions that can be lethal or seriously disabling to humans and animals. The knowledge of the anatomy and the pathology of the ENS represents a new important and fascinating topic, which deserves more attention in the veterinary medicine field.

Integrating omics in prion diseases as a model to explore the strain paradigm in neurodegenerative diseases

This project aims at deepening the understanding of the molecular basis of the phenotypic heterogeneity of prion diseases. Prion diseases represent the first and clearest example of “protein misfolding diseases”, that are all the neurodegenerative diseases caused by the accumulation of misfolded proteins in the central nervous system. In the field of protein misfolding diseases, the term “strain” describes the heterogeneity observed among the same disease in the clinical and pathologic progression, biochemical features of the aggregated protein, conformational memory and pattern of lesions. In this work, the two most common strains of Creutzfeldt-Jakob Disease (CJD), named MM1 and VV2, were analyzed. This thesis investigates the strain paradigm with the production of new multi omic data, and, on such data, appropriate computational analysis combining bioinformatics, data science and statistical approaches was performed. In this work, genomic and transcriptomic profiling allowed an improved characterization of the molecular features of the two most common strains of CJD, identifying multiple possible genetic contributors to the disease and finding several shared impaired pathways between the VV2 strain and Parkinson Disease. On the epigenomic level, the tridimensional chromatin folding in peripheral immune cells of CJD patients at onset and of healthy controls was investigated with Hi-C. While being the first application of this very advanced technology in prion diseases and one of the first in general in neurobiology, this work found a significant and diffuse loss of genomic interactions in immune cells of CJD patients at disease onset, particularly in the PRNP locus, suggesting a possible impairment of chromatin conformation in the disease. The results of this project represent a novelty in the state of the art in this field, both from a biomedical and technological point of view.

Development of functional MRI protocols in the study of neurodegenerative diseases: MRI study in patients with REM sleep behavior disorder, idiopathic Parkinson's disease and multisystem atrophy

In the central nervous system, iron in several proteins is involved in many important processes: oxygen transportation, oxidative phosphorylation, mitochondrial respiration, myelin production, the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation, modification of lipids, proteins, carbohydrates, and DNA, lead to neurotoxicity. Moreover increased levels of iron are harmful and iron accumulations are typical hallmarks of brain ageing and several neurodegenerative disorders particularly PD. Numerous studies on post mortem tissue report on an increased amount of total iron in the substantia nigra in patients with PD also supported by large body of in vivo findings from Magnetic Resonance Imaging (MRI) studies. The importance and approaches for in vivo brain iron assessment using multiparametric MRI is increased over last years. Quantitative MRI may provide useful biomarkers for brain integrity assessment in iron-related neurodegeneration. Particularly, a prominent change in iron- sensitive T2* MRI contrast within the sub areas of the SN overlapping with nigrosome 1 were shown to be a hallmark of Parkinson's Disease with high diagnostic accuracy. Moreover, differential diagnosis between Parkinson's Disease (PD) and atypical parkinsonian syndromes (APS) remains challenging, mainly in the early phases of the disease. Advanced brain MR imaging enables to detect the pathological changes of nigral and extranigral structures at the onset of clinical manifestations and during the course of the disease. The Nigrosome-1 (N1) is a substructure of the healthy Substantia Nigra pars compacta enriched by dopaminergic neurons; their loss in Parkinson’s disease and atypical parkinsonian syndromes is related to the iron accumulation. N1 changes are supportive MR biomarkers for diagnosis of these neurodegenerative disorders, but its detection is hard with conventional sequences, also using high field (3T) scanner. Quantitative susceptibility mapping (QSM), an iron-sensitive technique, enables the direct detection of Neurodegeneration

Design, synthesis and biological evaluation of dual inhibitors of GSK-3B and Fyn kinases for the study of inflammatory pathways in neurodegenerative diseases

Neuroinflammation represents a key hallmark of neurodegenerative diseases and is the result of a complex network of signaling cascades within microglial cells. A positive feedback loop exists between inflammation, microglia activation and protein misfolding processes, that, together with oxidative stress and excitotoxicity, lead to neuronal degeneration. Therefore, targeting this vicious cycle can be beneficial for mitigating neurodegeneration and cognitive decline in central nervous system disorders. At molecular level, GSK-3B and Fyn kinases play a crucial role in microglia activation and their deregulation has been associated to many neurodegenerative diseases. Thus, we envisioned their combined targeting as an effective approach to disrupt this toxic loop. Specifically in this project, a hit compound, based on a 7-azaindole-3-aminothiazole structure, was first identified in a virtual screening campaign, and displayed a weak dual inhibitory activity on GSK-3B and Fyn, unbalanced towards the former. Then, in a commitment to uncover the structural features required for modulating the activity on the two targets, we systematically manipulated this compound by inserting various substitution patterns in different positions. The most potent compounds obtained were advanced to deeper investigations to test their ability of tackling the inflammatory burden also in cellular systems and to unveil their binding modes within the catalytic pocket. The new class of molecules synthesized emerged as a valuable tool to deepen our understanding of the complex network governing the inflammatory events in neurodegenerative disorders.

The Value Of The 2005 International Society Of Urological Pathology (isup) Modified Gleason Grading System As A Predictor Of Biochemical Recurrence After Radical Prostatectomy.

To compare time and risk to biochemical recurrence (BR) after radical prostatectomy of two chronologically different groups of patients using the standard and the modified Gleason system (MGS). Cohort 1 comprised biopsies of 197 patients graded according to the standard Gleason system (SGS) in the period 1997/2004, and cohort 2, 176 biopsies graded according to the modified system in the period 2005/2011. Time to BR was analyzed with the Kaplan-Meier product-limit analysis and prediction of shorter time to recurrence using univariate and multivariate Cox proportional hazards model. Patients in cohort 2 reflected time-related changes: striking increase in clinical stage T1c, systematic use of extended biopsies, and lower percentage of total length of cancer in millimeter in all cores. The MGS used in cohort 2 showed fewer biopsies with Gleason score ≤ 6 and more biopsies of the intermediate Gleason score 7. Time to BR using the Kaplan-Meier curves showed statistical significance using the MGS in cohort 2, but not the SGS in cohort 1. Only the MGS predicted shorter time to BR on univariate analysis and on multivariate analysis was an independent predictor. The results favor that the 2005 International Society of Urological Pathology modified system is a refinement of the Gleason grading and valuable for contemporary clinical practice.

The Intrahippocampal Infusion Of Crotamine From Crotalus Durissus Terrificus Venom Enhances Memory Persistence In Rats.

Previous research has shown that crotamine, a toxin isolated from the venom of Crotalus durissus terrificus, induces the release of acetylcholine and dopamine in the central nervous system of rats. Particularly, these neurotransmitters are important modulators of memory processes. Therefore, in this study we investigated the effects of crotamine infusion on persistence of memory in rats. We verified that the intrahippocampal infusion of crotamine (1 μg/μl; 1 μl/side) improved the persistence of object recognition and aversive memory. By other side, the intrahippocampal infusion of the toxin did not alter locomotor and exploratory activities, anxiety or pain threshold. These results demonstrate a future prospect of using crotamine as potential pharmacological tool to treat diseases involving memory impairment, although it is still necessary more researches to better elucidate the crotamine effects on hippocampus and memory.

The Applicability Of Ordered Mesoporous Sba-15 And Its Hydrophobic Glutaraldehyde-bridge Derivative To Improve Ibuprofen-loading In Releasing System.

The mesoporous SBA-15 silica with uniform hexagonal pore, narrow pore size distribution and tuneable pore diameter was organofunctionalized with glutaraldehyde-bridged silylating agent. The precursor and its derivative silicas were ibuprofen-loaded for controlled delivery in simulated biological fluids. The synthesized silicas were characterized by elemental analysis, infrared spectroscopy, (13)C and (29)Si solid state NMR spectroscopy, nitrogen adsorption, X-ray diffractometry, thermogravimetry and scanning electron microscopy. Surface functionalization with amine containing bridged hydrophobic structure resulted in significantly decreased surface area from 802.4 to 63.0 m(2) g(-1) and pore diameter 8.0-6.0 nm, which ultimately increased the drug-loading capacity from 18.0% up to 28.3% and a very slow release rate of ibuprofen over the period of 72.5h. The in vitro drug release demonstrated that SBA-15 presented the fastest release from 25% to 27% and SBA-15GA gave near 10% of drug release in all fluids during 72.5 h. The Korsmeyer-Peppas model better fits the release data with the Fickian diffusion mechanism and zero order kinetics for synthesized mesoporous silicas. Both pore sizes and hydrophobicity influenced the rate of the release process, indicating that the chemically modified silica can be suggested to design formulation of slow and constant release over a defined period, to avoid repeated administration.

Electronic And Structural Study Of Pt-modified Au Vicinal Surfaces: A Model System For Pt-au Catalysts.

Two single crystalline surfaces of Au vicinal to the (111) plane were modified with Pt and studied using scanning tunneling microscopy (STM) and X-ray photoemission spectroscopy (XPS) in ultra-high vacuum environment. The vicinal surfaces studied are Au(332) and Au(887) and different Pt coverage (θPt) were deposited on each surface. From STM images we determine that Pt deposits on both surfaces as nanoislands with heights ranging from 1 ML to 3 ML depending on θPt. On both surfaces the early growth of Pt ad-islands occurs at the lower part of the step edge, with Pt ad-atoms being incorporated into the steps in some cases. XPS results indicate that partial alloying of Pt occurs at the interface at room temperature and at all coverage, as suggested by the negative chemical shift of Pt 4f core line, indicating an upward shift of the d-band center of the alloyed Pt. Also, the existence of a segregated Pt phase especially at higher coverage is detected by XPS. Sample annealing indicates that the temperature rise promotes a further incorporation of Pt atoms into the Au substrate as supported by STM and XPS results. Additionally, the catalytic activity of different PtAu systems reported in the literature for some electrochemical reactions is discussed considering our findings.

Inhibitory Effects Of A Cured Antibacterial Bonding System On Viability And Metabolic Activity Of Oral Bacteria.

To evaluate the antimicrobial efficacy of Clearfil SE Protect (CP) and Clearfil SE Bond (CB) after curing and rinsed against five individual oral microorganisms as well as a mixture of bacterial culture prepared from the selected test organisms. Bacterial suspensions were prepared from single species of Streptococcus mutans, Streptococcus sobrinus, Streptococcus gordonii, Actinomyces viscosus and Lactobacillus lactis, as well as mixed bacterial suspensions from these organisms. Dentin bonding system discs (6 mm×2 mm) were prepared, cured, washed and placed on the bacterial suspension of single species or multispecies bacteria for 15, 30 and 60 min. MTT, Live/Dead bacterial viability (antibacterial effect), and XTT (metabolic activity) assays were used to test the two dentin system's antibacterial effect. All assays were done in triplicates and each experiment repeated at least three times. Data were submitted to ANOVA and Scheffe's f-test (5%). Greater than 40% bacteria killing was seen within 15 min, and the killing progressed with increasing time of incubation with CP discs. However, a longer (60 min) period of incubation was required by CP to achieve similar antimicrobial effect against mixed bacterial suspension. CB had no significant effect on the viability or metabolic activity of the test microorganisms when compared to the control bacterial culture. CP was significantly effective in reducing the viability and metabolic activity of the test organisms. The results demonstrated the antimicrobial efficacy of CP both on single and multispecies bacterial culture. CP may be beneficial in reducing bacterial infections in cavity preparations in clinical dentistry.

Blockade Of Renin-angiotensin System Prevents Micturition Dysfunction In Renovascular Hypertensive Rats.

Association between hypertension and bladder symptoms has been described. We hypothesized that micturition dysfunction may be associated with renin-angiotensin system (RAS) acting in urethra. The effects of the anti-hypertensive drugs losartan (AT1 antagonist) and captopril (angiotensin-converting enzyme inhibitor) in comparison with atenolol (β1-adrenoceptor antagonist independently of RAS blockade) have been investigated in bladder and urethral dysfunctions during renovascular hypertension in rats. Two kidney-1 clip (2K-1C) rats were treated with losartan (30 mg/kg/day), captopril (50mg/kg/day) or atenolol (90 mg/kg/day) for eight weeks. Cystometric study, bladder and urethra smooth muscle reactivities, measurement of cAMP levels and p38 MAPK phosphorylation in urinary tract were determined. Losartan and captopril markedly reduced blood pressure in 2K-1C rats. The increases in non-voiding contractions, voiding frequency and bladder capacity in 2K-1C rats were prevented by treatments with both drugs. Likewise, losartan and captopril prevented the enhanced bladder contractions to electrical-field stimulation (EFS) and carbachol, along with the impaired relaxations to β-adrenergic-cAMP stimulation. Enhanced neurogenic contractions and impaired nitrergic relaxations were observed in urethra from 2K-1C rats. Angiotensin II also produced greater urethral contractions that were accompanied by higher phosphorylation of p38 MAPK in urethral tissues of 2K-1C rats. Losartan and captopril normalized the urethral dysfunctions in 2K-1C rats. In contrast, atenolol treatment largely reduced the blood pressure in 2K-1C rats but failed to affect the urinary tract smooth muscle dysfunction. The urinary tract smooth muscle dysfunction in 2K-1C rats takes place by local RAS activation irrespective of levels of arterial blood pressure.

Advancing Bag-of-visual-words Representations For Lesion Classification In Retinal Images.

Diabetic Retinopathy (DR) is a complication of diabetes that can lead to blindness if not readily discovered. Automated screening algorithms have the potential to improve identification of patients who need further medical attention. However, the identification of lesions must be accurate to be useful for clinical application. The bag-of-visual-words (BoVW) algorithm employs a maximum-margin classifier in a flexible framework that is able to detect the most common DR-related lesions such as microaneurysms, cotton-wool spots and hard exudates. BoVW allows to bypass the need for pre- and post-processing of the retinographic images, as well as the need of specific ad hoc techniques for identification of each type of lesion. An extensive evaluation of the BoVW model, using three large retinograph datasets (DR1, DR2 and Messidor) with different resolution and collected by different healthcare personnel, was performed. The results demonstrate that the BoVW classification approach can identify different lesions within an image without having to utilize different algorithms for each lesion reducing processing time and providing a more flexible diagnostic system. Our BoVW scheme is based on sparse low-level feature detection with a Speeded-Up Robust Features (SURF) local descriptor, and mid-level features based on semi-soft coding with max pooling. The best BoVW representation for retinal image classification was an area under the receiver operating characteristic curve (AUC-ROC) of 97.8% (exudates) and 93.5% (red lesions), applying a cross-dataset validation protocol. To assess the accuracy for detecting cases that require referral within one year, the sparse extraction technique associated with semi-soft coding and max pooling obtained an AUC of 94.2 ± 2.0%, outperforming current methods. Those results indicate that, for retinal image classification tasks in clinical practice, BoVW is equal and, in some instances, surpasses results obtained using dense detection (widely believed to be the best choice in many vision problems) for the low-level descriptors.