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This thesis should be read as an almost chronological account of the clinical problems we faced and subsequently investigated while we were treating the waves of COVID-19 patients in real-time. It combines multiple original investigations, narrative reviews, book chapters and research letters concerning the diagnosis, risk stratification, monitoring and complications of COVID-19 patients in the acute and critical care setting during the emerging and developing pandemic, with a special emphasis on the role of point-of-care ultrasound (POCUS). The thesis is divided into three main parts. Part 1 focuses on the use of conventional tests at the emergency department (ED) in the diagnosis and prognosis of COVID-19, as well as its complications. Part 2 explores how POCUS might aid in this setting. Part 3 addresses how POCUS might aid in monitoring of the disease course in critically ill COVID-19 patients. And how it might help diagnose COVID-19 complications in this setting.

The studies in this thesis explored the rationale and utility of clinical staging models in bipolar disorder. There is a need for further improvement of diagnostics in psychiatry to organize the broad range of clinical expressions, to promote a longitudinal as opposed to cross-sectional perspective, that allows for efficient communication, and may guide a personalized treatment approach. Clinical staging models are a way to operationalize illness progression and may provide a solution in overcoming these issues. Staging models have been introduced and tested for several psychiatric illnesses such as depression, schizophrenia, personality disorders, anxiety disorders, alcohol use disorder as well as a model for all major mental health disorders This thesis described one of the first attempts to explore the validity and applicability of two staging models specifically designed for bipolar disorders (BD). In this thesis, we tested the two predominant staging models for BD by applying them to clinical data. Berk et al. proposed a staging model based on the recurrence of mood episodes, in some chapters referred to as Model A. A second staging model, in some chapters referred to as Model B, was proposed by Kapczinski et al. and is based on impaired inter-episodic functioning. We used five different approaches to apply these staging models to both longitudinal as well as cross-sectional clinical data, leading to five publications. Additionally, with the Staging Taskforce of the International Society for Bipolar Disorders, we defined a standardized nomenclature for the staging of BD. Lastly, we explored the similarities and differences between our current views on illness progression with those from the late 19th and early 20th century.

MRI MRI proves to be a very helpful tool for physicians outside tertiary referral centers. Remarkably many physicians assess MR images themselves. In many outpatient clinics however, neurologists are the leading specialty in a multidisciplinary team and usually are a member of this team when other specialties are in the lead. Consultants neurology are trained in assessing MRI, consultants geriatric medicine and psychiatry usually are not. The still modest experience of many radiologists assessing potential signs of neurodegenerative disease, may be a reason that the physicians’ assessment is frequently used to make the consensus diagnosis. It will probably be helpful for radiologists to assess MRI in a standardized way, reporting on all relevant aspects of neurodegenerative disease by using scales to visually rate atrophy and white matter lesions. MRI proved to be useful in our practice, increasing confidence by around 10% on a VAS, which reflects a clinically significant increase.1-9 In our study the indications of confidence on the VAS will beforehand not be normally distributed. Very seldom a physician will only have a 10 or 20% confidence in a pre- or post MRI assessment. A 10% change in the left half of this distribution represents in a psychological sense a smaller change than the same amount in the right half of the distribution. In this way the result of a 10% increase represents a clinically relevant change. CSF The CSF tool also proves to be helpful in the diagnostic process outside a tertiary referral center. Results in the 3.1 and 3.2 study are comparable, with better results in the second study with regard to the number of diagnoses changed having CSF results available, as well as regarding the measure of increase in certainty. This is probably due to methodology; in 3.1 only for one patient no diagnosis was available pre-CSF. In 3.2 in a considerable number of patients a diagnosis was suspended. Only after presentation of CSF results a diagnosis was made. This may be a coincidence, it may also be the result of the availability of multiple biomarkers resulting in a tendency to postpone a diagnosis when in doubt. Furthermore, the mean age of subjects in 3.1 is 72, versus 67.9 years in 3.2. The 3.1 mean age falls in the oldest age category of 3.2, showing the least typical CSF profiles that match the clinical diagnosis. Neuropsychological tests In 4.1 we show that it pays off to adapt a test protocol to the needs of more senior subjects. These subjects need more time but also more encouragement to ensure the best possible performance. This sounds very straightforward but in everyday practice due to a lack of staff and consequently time, this condition is quite a challenge to meet. Number of missing data using the 15WT may not be reduced in AD dementia patients, even when a strict adherence to the test protocol is used. This illustrates the ineligibility for use of this test in this group of subjects. An interesting finding of the 4.2 study using the VAT extended version, is that memory performance of aMCI and AD dementia patients is much better when measured in a recognition mode in comparison to the direct free recall mode. This is important; aMCI and mild AD patients can learn new material in a visual associative learning paradigm. This presents caregivers and therapeutic professionals with an important tool to improve daily function and communication. It also questions the typical profile of AD patients, showing typically poor results in free recall and recognition conditions. A diagnosis of AD may still be taken into consideration despite normal or near normal recognition scores.

MRI MRI proves to be a very helpful tool for physicians outside tertiary referral centers. Remarkably many physicians assess MR images themselves. In many outpatient clinics however, neurologists are the leading specialty in a multidisciplinary team and usually are a member of this team when other specialties are in the lead. Consultants neurology are trained in assessing MRI, consultants geriatric medicine and psychiatry usually are not. The still modest experience of many radiologists assessing potential signs of neurodegenerative disease, may be a reason that the physicians’ assessment is frequently used to make the consensus diagnosis. It will probably be helpful for radiologists to assess MRI in a standardized way, reporting on all relevant aspects of neurodegenerative disease by using scales to visually rate atrophy and white matter lesions. MRI proved to be useful in our practice, increasing confidence by around 10% on a VAS, which reflects a clinically significant increase.1-9 In our study the indications of confidence on the VAS will beforehand not be normally distributed. Very seldom a physician will only have a 10 or 20% confidence in a pre- or post MRI assessment. A 10% change in the left half of this distribution represents in a psychological sense a smaller change than the same amount in the right half of the distribution. In this way the result of a 10% increase represents a clinically relevant change. CSF The CSF tool also proves to be helpful in the diagnostic process outside a tertiary referral center. Results in the 3.1 and 3.2 study are comparable, with better results in the second study with regard to the number of diagnoses changed having CSF results available, as well as regarding the measure of increase in certainty. This is probably due to methodology; in 3.1 only for one patient no diagnosis was available pre-CSF. In 3.2 in a considerable number of patients a diagnosis was suspended. Only after presentation of CSF results a diagnosis was made. This may be a coincidence, it may also be the result of the availability of multiple biomarkers resulting in a tendency to postpone a diagnosis when in doubt. Furthermore, the mean age of subjects in 3.1 is 72, versus 67.9 years in 3.2. The 3.1 mean age falls in the oldest age category of 3.2, showing the least typical CSF profiles that match the clinical diagnosis. Neuropsychological tests In 4.1 we show that it pays off to adapt a test protocol to the needs of more senior subjects. These subjects need more time but also more encouragement to ensure the best possible performance. This sounds very straightforward but in everyday practice due to a lack of staff and consequently time, this condition is quite a challenge to meet. Number of missing data using the 15WT may not be reduced in AD dementia patients, even when a strict adherence to the test protocol is used. This illustrates the ineligibility for use of this test in this group of subjects. An interesting finding of the 4.2 study using the VAT extended version, is that memory performance of aMCI and AD dementia patients is much better when measured in a recognition mode in comparison to the direct free recall mode. This is important; aMCI and mild AD patients can learn new material in a visual associative learning paradigm. This presents caregivers and therapeutic professionals with an important tool to improve daily function and communication. It also questions the typical profile of AD patients, showing typically poor results in free recall and recognition conditions. A diagnosis of AD may still be taken into consideration despite normal or near normal recognition scores.

MRI MRI proves to be a very helpful tool for physicians outside tertiary referral centers. Remarkably many physicians assess MR images themselves. In many outpatient clinics however, neurologists are the leading specialty in a multidisciplinary team and usually are a member of this team when other specialties are in the lead. Consultants neurology are trained in assessing MRI, consultants geriatric medicine and psychiatry usually are not. The still modest experience of many radiologists assessing potential signs of neurodegenerative disease, may be a reason that the physicians’ assessment is frequently used to make the consensus diagnosis. It will probably be helpful for radiologists to assess MRI in a standardized way, reporting on all relevant aspects of neurodegenerative disease by using scales to visually rate atrophy and white matter lesions. MRI proved to be useful in our practice, increasing confidence by around 10% on a VAS, which reflects a clinically significant increase.1-9 In our study the indications of confidence on the VAS will beforehand not be normally distributed. Very seldom a physician will only have a 10 or 20% confidence in a pre- or post MRI assessment. A 10% change in the left half of this distribution represents in a psychological sense a smaller change than the same amount in the right half of the distribution. In this way the result of a 10% increase represents a clinically relevant change. CSF The CSF tool also proves to be helpful in the diagnostic process outside a tertiary referral center. Results in the 3.1 and 3.2 study are comparable, with better results in the second study with regard to the number of diagnoses changed having CSF results available, as well as regarding the measure of increase in certainty. This is probably due to methodology; in 3.1 only for one patient no diagnosis was available pre-CSF. In 3.2 in a considerable number of patients a diagnosis was suspended. Only after presentation of CSF results a diagnosis was made. This may be a coincidence, it may also be the result of the availability of multiple biomarkers resulting in a tendency to postpone a diagnosis when in doubt. Furthermore, the mean age of subjects in 3.1 is 72, versus 67.9 years in 3.2. The 3.1 mean age falls in the oldest age category of 3.2, showing the least typical CSF profiles that match the clinical diagnosis. Neuropsychological tests In 4.1 we show that it pays off to adapt a test protocol to the needs of more senior subjects. These subjects need more time but also more encouragement to ensure the best possible performance. This sounds very straightforward but in everyday practice due to a lack of staff and consequently time, this condition is quite a challenge to meet. Number of missing data using the 15WT may not be reduced in AD dementia patients, even when a strict adherence to the test protocol is used. This illustrates the ineligibility for use of this test in this group of subjects. An interesting finding of the 4.2 study using the VAT extended version, is that memory performance of aMCI and AD dementia patients is much better when measured in a recognition mode in comparison to the direct free recall mode. This is important; aMCI and mild AD patients can learn new material in a visual associative learning paradigm. This presents caregivers and therapeutic professionals with an important tool to improve daily function and communication. It also questions the typical profile of AD patients, showing typically poor results in free recall and recognition conditions. A diagnosis of AD may still be taken into consideration despite normal or near normal recognition scores.

MRI MRI proves to be a very helpful tool for physicians outside tertiary referral centers. Remarkably many physicians assess MR images themselves. In many outpatient clinics however, neurologists are the leading specialty in a multidisciplinary team and usually are a member of this team when other specialties are in the lead. Consultants neurology are trained in assessing MRI, consultants geriatric medicine and psychiatry usually are not. The still modest experience of many radiologists assessing potential signs of neurodegenerative disease, may be a reason that the physicians’ assessment is frequently used to make the consensus diagnosis. It will probably be helpful for radiologists to assess MRI in a standardized way, reporting on all relevant aspects of neurodegenerative disease by using scales to visually rate atrophy and white matter lesions. MRI proved to be useful in our practice, increasing confidence by around 10% on a VAS, which reflects a clinically significant increase.1-9 In our study the indications of confidence on the VAS will beforehand not be normally distributed. Very seldom a physician will only have a 10 or 20% confidence in a pre- or post MRI assessment. A 10% change in the left half of this distribution represents in a psychological sense a smaller change than the same amount in the right half of the distribution. In this way the result of a 10% increase represents a clinically relevant change. CSF The CSF tool also proves to be helpful in the diagnostic process outside a tertiary referral center. Results in the 3.1 and 3.2 study are comparable, with better results in the second study with regard to the number of diagnoses changed having CSF results available, as well as regarding the measure of increase in certainty. This is probably due to methodology; in 3.1 only for one patient no diagnosis was available pre-CSF. In 3.2 in a considerable number of patients a diagnosis was suspended. Only after presentation of CSF results a diagnosis was made. This may be a coincidence, it may also be the result of the availability of multiple biomarkers resulting in a tendency to postpone a diagnosis when in doubt. Furthermore, the mean age of subjects in 3.1 is 72, versus 67.9 years in 3.2. The 3.1 mean age falls in the oldest age category of 3.2, showing the least typical CSF profiles that match the clinical diagnosis. Neuropsychological tests In 4.1 we show that it pays off to adapt a test protocol to the needs of more senior subjects. These subjects need more time but also more encouragement to ensure the best possible performance. This sounds very straightforward but in everyday practice due to a lack of staff and consequently time, this condition is quite a challenge to meet. Number of missing data using the 15WT may not be reduced in AD dementia patients, even when a strict adherence to the test protocol is used. This illustrates the ineligibility for use of this test in this group of subjects. An interesting finding of the 4.2 study using the VAT extended version, is that memory performance of aMCI and AD dementia patients is much better when measured in a recognition mode in comparison to the direct free recall mode. This is important; aMCI and mild AD patients can learn new material in a visual associative learning paradigm. This presents caregivers and therapeutic professionals with an important tool to improve daily function and communication. It also questions the typical profile of AD patients, showing typically poor results in free recall and recognition conditions. A diagnosis of AD may still be taken into consideration despite normal or near normal recognition scores.

Healthcare is a highly complex and dynamic sector. Although it features many typical market dynamics and rules the healthcare sector is prone to product and market failure (Toumi, 2017). It is therefore of utmost importance that healthcare regulation and resource allocation is purposeful, maximises the utility of available care options at the right point in time and is (considered) fair. As immunisation is an excellent public health tool that can protect entire populations from harm, it is particularly important that introduction decisions are based on transparent and accountable evaluation procedures. We demonstrate that it is possible to establish a vaccine expert-based consensus on a core set of decision criteria (priorities) to be taken into consideration by NITAG members in their vaccine introduction decision procedures. We also demonstrate that including these priorities in SMART Vaccines, a vaccine specific multi-criteria decision analysis (MCDA) tool, would substantially increase the transparency and accountability for reasonableness of SMART Vaccines-based decision procedures. As personalised care and prevention are being recognised as the central plank of dealing with increasing healthcare expenditures, and the primary care setting is ideal for early detection and prevention or postponement of many (non-communicable) diseases, we developed a roadmap concept for re-orienting, in a first step, the primary care health system. Naturally, mobile and smart diagnostics, devices and applications, to be utilised outside of the clinical setting, can facilitate the collection of real-world data in so-called virtual clinical trials (VCTs). However, VCTs are not commonplace as of yet, in particular in Europe. We found that challenges pertinent to general awareness, technical validation and usability of smart devices, data processing, regulatory review, and suboptimal collaboration of stakeholders persist and prevent the broad adoption of VCTs. The findings of the VCT study also highlight some potential challenges but also facilitators for the adoption of the dMC concept. Some challenges identified in the VCT study, in particular those relating to user-centred product design and stakeholder information/data needs, could also be largely addressed by the proper collection and analysis of market intelligence. As even basic market research is not commonly performed by academic entrepreneurs and SMEs and lack in expertise and resources is a prominent barrier, we elicited from experts which market research considerations they consider particularly important and created a market research toolbox for the biopharmaceutics sector. A common theme across all considerations is information asymmetry of innovators towards important stakeholders. Conversely, and in particular in emerging technology fields, R&D activities can outpace regulatory oversight. Currently, there exists paucity of regulatory protocol harmonisation regarding the review of marketing authorisation submissions for live biotherapeutic products (LBPs) – including health claims – in Europe and the USA. To reverse the rationale of the previous study, we collected information from innovators, namely recent patenting activity, to cross-inform regulators of potentially upcoming LBP-technologies that might require regulatory oversight in the near-to mid-term future. We found that overall patenting activity for LBPs is in decline, and heavily concentrated on the Chinese market. Despite the decline, we identified some prominent relative increases for less expected targets. Involving affected stakeholders in innovation processes and exploiting various means to decrease information asymmetry among them can considerably increase resource utilisation efficiency, focus resources on areas that require further research and thereby close knowledge gaps, and reduce frustration and friction caused by exclusive health decision making criteria. Involving and empowering all affected stakeholders to take part in various innovation-related processes and in particular providing patients with the technological means and literacy to better maintain and improve their own health and autonomy, are of paramount importance for the future.

Healthcare is a highly complex and dynamic sector. Although it features many typical market dynamics and rules the healthcare sector is prone to product and market failure (Toumi, 2017). It is therefore of utmost importance that healthcare regulation and resource allocation is purposeful, maximises the utility of available care options at the right point in time and is (considered) fair. As immunisation is an excellent public health tool that can protect entire populations from harm, it is particularly important that introduction decisions are based on transparent and accountable evaluation procedures. We demonstrate that it is possible to establish a vaccine expert-based consensus on a core set of decision criteria (priorities) to be taken into consideration by NITAG members in their vaccine introduction decision procedures. We also demonstrate that including these priorities in SMART Vaccines, a vaccine specific multi-criteria decision analysis (MCDA) tool, would substantially increase the transparency and accountability for reasonableness of SMART Vaccines-based decision procedures. As personalised care and prevention are being recognised as the central plank of dealing with increasing healthcare expenditures, and the primary care setting is ideal for early detection and prevention or postponement of many (non-communicable) diseases, we developed a roadmap concept for re-orienting, in a first step, the primary care health system. Naturally, mobile and smart diagnostics, devices and applications, to be utilised outside of the clinical setting, can facilitate the collection of real-world data in so-called virtual clinical trials (VCTs). However, VCTs are not commonplace as of yet, in particular in Europe. We found that challenges pertinent to general awareness, technical validation and usability of smart devices, data processing, regulatory review, and suboptimal collaboration of stakeholders persist and prevent the broad adoption of VCTs. The findings of the VCT study also highlight some potential challenges but also facilitators for the adoption of the dMC concept. Some challenges identified in the VCT study, in particular those relating to user-centred product design and stakeholder information/data needs, could also be largely addressed by the proper collection and analysis of market intelligence. As even basic market research is not commonly performed by academic entrepreneurs and SMEs and lack in expertise and resources is a prominent barrier, we elicited from experts which market research considerations they consider particularly important and created a market research toolbox for the biopharmaceutics sector. A common theme across all considerations is information asymmetry of innovators towards important stakeholders. Conversely, and in particular in emerging technology fields, R&D activities can outpace regulatory oversight. Currently, there exists paucity of regulatory protocol harmonisation regarding the review of marketing authorisation submissions for live biotherapeutic products (LBPs) – including health claims – in Europe and the USA. To reverse the rationale of the previous study, we collected information from innovators, namely recent patenting activity, to cross-inform regulators of potentially upcoming LBP-technologies that might require regulatory oversight in the near-to mid-term future. We found that overall patenting activity for LBPs is in decline, and heavily concentrated on the Chinese market. Despite the decline, we identified some prominent relative increases for less expected targets. Involving affected stakeholders in innovation processes and exploiting various means to decrease information asymmetry among them can considerably increase resource utilisation efficiency, focus resources on areas that require further research and thereby close knowledge gaps, and reduce frustration and friction caused by exclusive health decision making criteria. Involving and empowering all affected stakeholders to take part in various innovation-related processes and in particular providing patients with the technological means and literacy to better maintain and improve their own health and autonomy, are of paramount importance for the future.

Samenvatting Diagnostiek gaat over kwaliteitsvol oordelen en handelen in het belang van de cliënt. Wanneer je werkt met kinderen is dat een hele uitdaging! Hoe organiseer en weeg je de informatie van ouders, leerkrachten en zorgverleners? Hoe vermijd je dat oordelen meer jouw gevoelens spiegelen dan die van het gezin en het kind? Als professioneel behandelaar krijgt je brein veel te verwerken. Je moet weten wat je doet, waarom je het doet en hoe het moet volgens de beroepseisen. Diagnostiek van kind, opvoeding en gezin leert je van aanmelding tot rapportage te diagnosticeren met de FACE©-methode. Je krijgt meerdere tools aangereikt om het draagvlak van het kind, de opvoeding en het gezin daadkrachtig in kaart te brengen. Dit biedt je handvatten om de veerkracht en verandering te onderkennen die de psychologische balans kan herstellen, zodat je de kinderen en hun omgeving verder kunt helpen. Dit handboek bouwt voort op Observeren en rapporteren, dat ook op de FACE©-methode is gebaseerd Doelgroep Dit boek is geschikt voor eerstejaars psychologiestudenten in het hoger (beroeps)onderwijs, bijvoorbeeld bij de opleidingen (toegepaste) psychologie, orthopedagogiek en sociale wetenschappen., Samenvatting Diagnostiek van kinderen is een kwestie van vragen en antwoorden over ontwikkeling, opvoeding, gezin, onderwijs, uitdagingen en veerkracht. Het is puzzelen om in de wirwar van klachten en krachten een zinvol geheel te ontcijferen waarmee je het kind en zijn omgeving verder kunt helpen. Het is communiceren met ouders, jongeren, collega’s en betrokken derden over problemen en -oplossingen. De ervaring leert dat het voor zowel studenten als professionals een uitdaging blijft om wetenschappelijke kennis zelfstandig te vertalen naar de praktijk. Dit leidt vaak tot een kloof tussen hoe de diagnostiek met het kind hoort te lopen en hoe ze in werkelijkheid loopt. Dit boek doelt bij te dragen tot het dichten van deze kloof met het FACE-model, een evidencebased methode die je werkwijzen en tools aanreikt om duidelijk en goed onderbouwd te diagnosticeren. Met tools zoals het Psychological Balance en het FACE'ogram leer je ‘hoe werkt diagnostiek’ en ‘hoe komt het dat het vaak niet lukt’ daadkrachtigte vertalen naar de praktijk met het kind en het gezin. Door middel van bottom-up didactiek (her)ontdek je wat typerend is voor je eigen diagnostische denken, voelen en doen, en hoe dit aangepast kan worden. De auteurs geven cases uit de complexe praktijk en spelen in op digitale flexibiliteit door online training, extra verdieping en een modulaire aanpak op specialisatieniveau aan te bieden. Dit handboek bouwt voort op Observeren en rapporteren, dat ook op de FACE-methode is gebaseerd. Doelgroep Dit boek is geschikt voor eerstejaars psychologiestudenten in het hoger (beroeps)onderwijs, bijvoorbeeld bij de opleidingen (toegepaste) psychologie, orthopedagogiek en sociale wetenschappen.