Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Protein phosphatase 1 (PP1) is an essential protein Ser/Thr phosphatase, which regulates various cellular processes in eukaryotic cells. The activity and substrate specificity of PP1 is strictly controlled by associated polypeptides, which are known as Regulatory Interactors of Protein Phosphatase One (RIPPOs). Currently, more than 200 RIPPOs have been described, all acting as subcellular targeting subunits, substrate recruiters, and/or activity modulators for associated PP1. Knowledge of the physiological substrates of each individual PP1 holoenzymes would massively enhance the functional understanding of these complexes. At the start of my research project, a straightforward strategy for substrate mapping of PP1 holoenzymes was not available. In the first part of my PhD project, I developed a tool to trap substrates of individual PP1:RIPPO holoenzymes. I found that a fusion of an hypoactive point mutant of PP1 and a RIPPO accumulates with its associated substrate, due to a lack of efficient dephosphorylation. The associated substrates were subsequently trapped and identified by Mass Spectrometry analysis. The identified substrates (novel and known proteins) were independently validated by in vitro dephosphorylation experiments. In this way, I performed substrate trapping, followed by substrate identification, for PP1:NIPP1, PP1:PNUTS, PP1:MYPT and PP1:RepoMan holoenzymes using the corresponding hypoactive PP1-RIPPO fusions. Furthermore, I found that RepoMan itself was a substrate of associated PP1. Together, my results suggest that hypoactive fusions represent an easy-to-use tool for substrate identification of multimeric protein Ser/Thr phosphatases individual holoenzymes.

Academic collection

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Academic collection

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Academic collection

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease that has a crude impact on a person's ability to breathe freely due to the progressive accumulation of scar tissue which destructs lung tissue. As a result, patients face debilitating symptoms such as breathlessness and fatigue, and are given a poor prognosis of two to five years after diagnosis if left untreated. Fortunately, there are two anti-fibrotic drugs available that positively impact the survival rate by slowing down disease progression. Nevertheless, the disease is still fatal and despite the positive effects of the medication on disease progression, patients continue to suffer from disease symptoms and experience a reduced quality of life. In addition, the medication needs to be taken long-term and often causes deleterious side effects such as gastrointestinal problems or phototoxicity which need to be managed adequately. On top of that, patients need to manage their psychological wellbeing, preserve a high social integration, and adapt their lifestyle or implement new behaviours such as staying physically active, applying sun protection, and limiting their alcohol use.Since IPF is a chronic illness, patients with IPF and their caregivers need a care system which addresses their individual multidimensional needs, including behavioural needs, values, and preferences (i.e., person-centred) and which subsequently organizes, and coordinates tailored care services by integrating various specialists across settings (i.e., integrated). At this moment, however, the IPF care systems mainly address medical and pharmacological care needs, while less attention is paid to other unique care needs of patients. Moreover, adequate coordination of care whereby multidisciplinary care teams across settings join hands in the patient's care is rather the exception, than the rule.Given the various challenges faced by patients, healthcare professionals and care systems in dealing with IPF disease, and the fact that we all want the highest quality care for the patients, the question arises as to whether the current care processes need to be rethought and redesigned to provide the person-centred integrated care that patients and informal caregivers need. This is the central question we have investigated in this doctoral work. We particularly focused on the IPF care model at the University Hospitals Leuven as this is one of the three Belgian centres of expertise for IPF diagnosis and management. Also, we used the Chronic Care Model (CCM) as theoretical framework to underpin the inquiry as this model helps researchers and healthcare professionals to reassess and organize the care delivery for chronically ill persons.In a first phase, we thoroughly assessed the current care and the needs of patients with IPF, their informal caregivers and the healthcare professionals involved in the care using a mixed methods approach. More specifically, we conducted a systematic literature review to identify care models/components that have been developed to address the multidimensional care needs of IPF patients (chapter 2). We performed one-on-one in-depth interviews with patients, caregiver and healthcare professionals involved in IPF care to gather their experiences and needs regarding IPF care (chapter 3). We also conducted an observational prospective study to gather insights on patients' psychological and behavioural needs, including medication adherence (chapter 4 and 5). Our results show that there are challenges related to health literacy, adherence to sun protection recommendations (to manage the phototoxic side effect of pirfenidone), psychological well-being, alcohol consumption, physical activity, and weight management. We also observed that patients face issues with taking their medication as prescribed, as measured by electronic monitoring, and our findings underscore the negative impact medication nonadherence might have on lung function outcomes. Moreover, several suggestions were mentioned during the interviews to provide pro-active care to act upon individual patients' needs and to expand the team-based multidisciplinary care with an extended role for the nurse. However, a lack of resources was also reported which hampers the involvement of other disciplines such as psychologists and dieticians. Hence, there are opportunities to build bridges and create formal collaborations with community services or healthcare professionals across settings and care levels. Furthermore, we observed a need for a structured care strategy for advance care planning, adherence support, self-management service and behavioural support, among others. In conclusion, despite the limited evidence available in the IPF literature, we noted opportunities to redesign the physician-centred acute care model to person-centred integrated care.Subsequently, in a second phase, we worked together with stakeholders, including patient representatives to prioritize the opportunities for change (chapter 6), to gather ideas on how to improve the care based on the priorities and to rank order the proposed ideas (chapter 7). As a result, we propose care components that should be integrated in the current IPF care to set the course for person-centred integrated care. These include the screening and assessment of patients' needs and wish for support, the use of individual care plans developed with the patient and caregiver, and the implementation and follow-up of the action points from the care plan. The important role of advanced practice nurses is emphasised as well as the establishment of networks of expertise (chapter 8).Altogether, based on our work and in line with principles of person-centred integrated care, we propose elements and goals to be further pursued in research and in routine IPF care, which should be underpinned by stakeholder involvement. These elements refer to placing patients with IPF and their informal caregivers at the centre of the care system, whereby care services are organized according to their individual needs, preferences, and values. In the newly designed integrated care model, a trained and coordinated IPF multidisciplinary team provides the care with the (advanced practice) nurse playing a pivotal role in care coordination activities, nurse-led care, and as the contact point for patients. Moreover, in the new model of care, there are streamlined referral systems and services with community resources and health professionals from other disciplines and across settings, where all actors are adequately informed about IPF and have the core competencies to care for patients with IPF and their informal caregivers. The interaction between the care teams and the IPF patient/informal caregiver is based on person-centred communication and relationships of trust are built. High-quality long-term accessible care, including self-management support is provided. The care is aligned to patients' needs, values, preferences and health literacy level as well as coordinated and integrated with these community services and healthcare professionals from other disciplines and across settings. Importantly, there is a clinical information system adapted for IPF care which supports the delivery of care (e.g., by integrated evidence-based guidelines) and facilitates the measurement of outcomes that matter to patients. Lastly, the importance of patient advocacy groups and peer support groups is emphasised, with initiatives being sought to better involve these groups in supporting patients and carers.

Academic collection

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

During the 20th century coal workers' pneumoconiosis-or anthraco-silicosis-and asbestos-related diseases were the major occupational respiratory diseases among Belgian workers, both in terms of public health impact as well as public visibility. Except for asbestos-induced mesothelioma, the occurrence of these occupational diseases has been declining in recent decades, due to improved prevention but to a large extent also because many hazardous industries, such as coal mining, were closed or have moved to the global south. In Europe, this has led many to think that occupational respiratory diseases can be considered diseases 'of the past'.However, workplace exposures do still contribute substantially to respiratory diseases. By bridging the gaps between the clinic, the university and the workplace, we can increase our understanding and improve the prevention of adverse health effects of occupational exposure to hazardous agents. This PhD project focuses on three topics, all requiring a different research approach: (1) the search for a cause of an enigmatic disease-sarcoidosis, (2) the re-emergence of an "old" disease in a new industry-silicosis in artificial stone workers, and (3) respiratory health effects of cleaning products in domestic cleaners.(1) Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs. The lungs and intrathoracic lymph nodes are the most commonly affected organs, but also the eyes, skin, liver, spleen, heart, and other organs can be involved. It is unclear what causes sarcoidosis. Several lines of evidence indicate that the disease results from an immune reaction in genetically susceptible persons upon exposure to one or several antigens. Many occupational and environmental exposures have been associated to sarcoidosis: inhaled organic dust, inorganic dust-including metals and minerals-and infectious agents-such as mycobacteria and Cutibacterium acnes. The diverse clinical manifestations and the wide range of associated exposures fuel the hypothesis that sarcoidosis has more than one cause, each of which may promote a different disease phenotype. However, the relationship between exposure and disease phenotype has barely been studied.In a retrospective study of 238 sarcoidosis patients, we showed that different occupational and environmental exposures are associated with different organ involvements. Sarcoidosis limited to pulmonary involvement was associated with exposure to inorganic dust prior to diagnosis (odds ratio [OR] 2.11; 95% confidence interval [CI] 1.11-4.17). Patients with liver involvement had higher odds of contact with livestock (OR 3.68; 95%CI 0.91-12.7) or having jobs with close human contact (OR 4.33; 95%CI 1.57-11.3) than patients without liver involvement. Similar associations were found for splenic involvement (livestock: OR 4.94, 95%CI 1.46-16.1; close human contact: OR 3.78; 95%CI 1.47-9.46). Cardiac sarcoidosis was associated with exposure to reactive chemicals (OR 5.08; 95%CI 1.28-19.2) or livestock (OR 9.86; 95%CI 1.95-49.0). Active smokers had more ocular sarcoidosis (OR 3.26; 95%CI 1.33-7.79).(2) In recent years, outbreaks of silicosis in artificial stone workers have been reported around the globe. Artificial stones consist of a very high percentage of crystalline silica (70-95% quartz or cristobalite) bound together with synthetic resins. They are increasingly used to make kitchen or bathroom countertops. For the workers who process the stones, the risk of silicosis is particularly high because the grinding and cutting of these stones generates high concentrations of respirable particles of crystalline silica. In Belgian artificial stone workers, silicosis has been probably underdetected. Via the clinic for occupational and environmental medicine in the University Hospitals Leuven, we initially confirmed silicosis in two referred workers from a 2-man company in the province of Antwerp, Belgium, which were the first cases reported in Belgium.We also describe an outbreak at a company producing silica-based artificial kerbstones-that were made for hygienic wall protection in the food industry-suggesting that silica-based artificial stones might have more applications than we had previously assumed. We report on 5 workers-of whom 4 had developed definite silicosis. Annual spirometries-but no chest X-rays-had been performed since 8 to 10 years prior to diagnosis. The four men with silicosis proved to have undergone an excessively rapid FEV1 decline [between 98 (95%CI 79-116) and 221 mL/year (95%CI 214-228)], many years before their first symptoms appeared. High respirable quartz concentrations (>0.1 mg/m³) were measured during various operations, especially during dry finishing of the cured kerbstones (1.080 mg/m³).The discovery of rapidly progressive serious lung disease in workers producing silica-based artificial kerbstones shows that the hazards of artificial stone production/processing reach beyond the kitchen/bathroom countertop industry. Increasing awareness, improving prevention and establishing workers' health surveillance programmes-or improving the quality of existing programmes-are crucial.(3) Professional domestic cleaners have an increased risk of asthma-like and other respiratory symptoms and conditions-which has been associated with the use of bleach, ammonia, disinfectants, and sprays. There is, however, uncertainty about which products are most hazardous. We did a questionnaire-based cross-sectional study in the Belgian service voucher sector to investigate, among professional domestic cleaners, the associations of the use of 40 types of cleaning products at work (liquids and sprays) with the occurrence of work-related eye and respiratory outcomes (eye symptoms, rhinitis, sore throat, inducible laryngeal obstruction, asthma and cough) and with chronic bronchitis. We defined "work-relatedness" as symptoms that disappear or improve on days off-work-which has been shown to be a typical clinical feature of work-related asthma and rhinitis.Among 1,586 domestic cleaners, the total number of cleaning sprays used per week (median 12/week) was significantly associated with all studied respiratory outcomes, with odds ratios ranging from 1.016 to 1.038 per spray per week. Bleach/disinfectant-containing liquid products were associated with work-related eye symptoms (OR 1.100 per product per week; 95%CI 1.017-1.190) and asthma (OR 1.104; 95%CI 1.008-1.208); liquid ammonia with chronic bronchitis (OR 1.463; 95%CI 1.053-2.035). Using elastic net regression, we identified several specific types of products that were strongly related to respiratory outcomes, such as mould removal sprays and carpet/seat/curtain sprays. Notably, cleaners capable of choosing their own products had fewer work-related eye symptoms (OR 0.758; 95%CI 0.576-0.996), rhinitis (OR 0.746; 95%CI 0.578-0.963) or cough (OR 0.697; 95%CI 0.539-0.901), suggesting that empowering domestic cleaners to choose their products may reduce the burden of symptoms.

Academic collection