Mutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic... Show moreMutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic approach that allows production of a shorter but functional protein. As DMD causing mutations can affect most of the 79 exons encoding dystrophin, a wide variety of AONs are needed to treat the patient population. Design of AONs is largely guided by trial-and-error, and it is yet unclear what defines the skippability of an exon. Here, we use a library of phosphorodiamidate morpholino oligomer (PMOs) AONs of similar physical properties to test the skippability of a large number of DMD exons. The DMD transcript is non-sequentially spliced, meaning that certain introns are retained longer in the transcript than downstream introns. We tested whether the relative intron retention time has a significant effect on AON efficiency, and found that targeting an out-of-frame exon flanked at its 5'-end by an intron that is retained in the transcript longer ('slow' intron) leads to overall higher exon skipping efficiency than when the 5'-end flanking intron is 'fast'. Regardless of splicing speed of flanking introns, we find that positioning an AON closer to the 5'-end of the target exon leads to higher exon skipping efficiency opposed to targeting an exons 3'-end. The data enclosed herein can be of use to guide future target selection and preferential AON binding sites for both DMD and other disease amenable by exon skipping therapies. Show less
During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully... Show moreDuring the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI's), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI's on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI's to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI's was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman's correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was -0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was -0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months. Show less
Borm, F.J.; Smit, J.; Bakker, J.; Wondergem, M.; Smit, E.F.; Langen, A.J. de; Gruijl, T.D. de 2023
Better biomarkers for programmed death - (ligand) 1 (PD-(L)1) checkpoint blockade in non-small cell lung cancer (NSCLC) are needed. We explored the predictive value of early response evaluation... Show moreBetter biomarkers for programmed death - (ligand) 1 (PD-(L)1) checkpoint blockade in non-small cell lung cancer (NSCLC) are needed. We explored the predictive value of early response evaluation using Fluor-18-deoxyglucose positron emission tomography and pre- and on-treatment flowcytometric T-cell profiling in peripheral blood and tumor-draining lymph nodes (TDLN). The on-treatment evaluation was performed 7–14 days after the start of PD-1 blockade in NSCLC patients. These data were related to (pathological) tumor response, progression-free survival, and overall survival (OS). We found that increases in total lesion glycolysis (TLG) had a strong reverse correlation with OS (r = −0.93, p = 0.022). Additionally, responders showed decreased and progressors increased Treg frequencies on-treatment. Frequencies of detectable PD-1-expressing CD8+ T cells decreased in responders but remained stable in progressors. This was especially found in the TDLN. Changes in activated Treg rates in TDLN were strongly but, due to low numbers of data points, non-significantly correlated with ΔTLG and reversely correlated with OS. Show less
Schootbrugge-vandermeer, H.J. van de; Kooyker, A.I.; Wisse, P.H.A.; Nagtegaal, I.D.; Geuzinge, H.A.; Toes-Zoutendijk, E.; ... ; Leerdam, M.E. van 2023
Background In the Dutch colorectal (CRC) screening program, fecal immunochemical test (FIT)-positive individuals are referred for colonoscopy. If no relevant findings are detected at colonoscopy,... Show moreBackground In the Dutch colorectal (CRC) screening program, fecal immunochemical test (FIT)-positive individuals are referred for colonoscopy. If no relevant findings are detected at colonoscopy, individuals are reinvited for FIT screening after 10 years. We aimed to assess CRC risk after a negative colonoscopy in FIT-positive individuals.Methods In this cross-sectional cohort study, data were extracted from the Dutch national screening information system. Participants with a positive FIT followed by a negative colonoscopy between 2014 and 2018 were included. A negative colonoscopy was defined as a colonoscopy during which no more than one nonvillous, nonproximal adenoma < 10 mm or serrated polyp < 10 mm was found. The main outcome was interval post-colonoscopy CRC (iPCCRC) risk. iPCCRC risk was reviewed against the risk of interval CRC after a negative FIT (FIT IC) with a 2-year screening interval.Results 35 052 FIT-positive participants had a negative colonoscopy and 24 iPCCRCs were diagnosed, resulting in an iPCCRC risk of 6.85 (95 %CI 4.60–10.19) per 10 000 individuals after a median follow-up of 1.4 years. After 2.5 years of follow-up, age-adjusted iPCCRC risk was approximately equal to FIT IC risk at 2 years.Conclusion Risk of iPCCRC within a FIT-based CRC screening program was low during the first years after colonos-copy but, after 2.5 years, was the same as the risk in FIT-negative individuals at 2 years, when they are reinvited for screening. Colonoscopy quality may therefore require further improvement and FIT screening interval may need to be reduced after negative colonoscopy. Show less
Background Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ... Show moreBackground Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with lowrisk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. Methods For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. Findings Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1–17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04–3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55–2·36; p=0·72). Interpretation The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. Show less
Purpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory... Show morePurpose The purpose of this study was to explore the lived experience of dancing with Parkinson's and Multiple Sclerosis in an inclusive dance group called ReDiscoverMe (RDM). Methods Participatory research approaches and interpretative phenomenological analysis were used to make sense of the lived experience captured in interviews and observations. Arthur Frank's conceptual framework on embodied storytelling from his book The Wounded Storyteller was the study's theoretical lens. Themes are both described and represented in images made by an RDM participant. Findings Dancing in a nonjudgmental environment was described by participants as a way to rediscover themselves while continually adapting to living with chronic illness. We interpreted this experience of rediscovery as an active, recursive process involving three "movements": escaping, expanding, and embracing. Through these movements, participants could rise above the self and illness. Conclusions The lived experience of dancing in this group was characterized by transformations of the body, self, and life. Through escaping, expanding, and embracing, participants could more easily embrace the body's contingency, integrate the self and body by becoming dancers, connect with others living with illness, and produce desire through passion. Participants could therefore experience illness as a journey and gain something from the experience. Show less
Vlegel-Brouwer, W. van der; Eelderink, M.; Bussemaker, J. 2023
Introduction: Ignited by the persistent health inequalities many cities and neighbourhoods, the ‘Healthy and Happy The Hague’ network in the Netherlands wanted to gain insight in how prevention and... Show moreIntroduction: Ignited by the persistent health inequalities many cities and neighbourhoods, the ‘Healthy and Happy The Hague’ network in the Netherlands wanted to gain insight in how prevention and health promotion could become successful in one deprived neighbourhood, Moerwijk. Methods: The cycle of Look-Think-Act of Participatory Action Research was used in which both citizens and professionals got involved from the start. Besides interviews, field notes were analysed, visualised and discussed in several rounds of focus groups. Results: Thematic analysis yielded seven themes: Healthy Eating and Exercise, Healthy Money, Healthy Mind, Healthy Relationships, Growing up healthy, Healthy Environment and Healthy Collaboration. During sessions around combination of themes, eight initiatives were co-created by citizens and professionals together, improving the feeling of ownership and interconnectedness. Discussion and conclusion: This PAR sheds a light on the mismatch between the system world’s solutions for individuals and the living world’s needs for solutions for the collective. Findings provides a better insight into the social, political, and cultural mechanisms and processes that influence clustering and interaction of health conditions. PAR is a promising process of citizens and professionals working together is an excellent way to learn about the conditions under which people experience health inequalities, and how to combat these inequalities. Show less
Background Lifestyle intervention programmes target behavioural risk factors that contribute to cardiovascular diseases (CVDs). Unfortunately, sustainable implementation of these programmes can be... Show moreBackground Lifestyle intervention programmes target behavioural risk factors that contribute to cardiovascular diseases (CVDs). Unfortunately, sustainable implementation of these programmes can be challenging. Gaining insights into the barriers and facilitators for successful implementation is important for maximising public health impact of these interventions. The Healthy Heart (HH) programme is an example of a combined lifestyle intervention programme.Aim To analyse the reach, adoption, and implementation of the HH programme.Design & setting A mixed-methods study conducted in a general practice setting in The Netherlands.Method Quantitative data were collected from the Healthy Heart study (HH study), a non-randomised cluster stepped-wedge trial to assess the effect of the HH programme on patients at high risk of developing CVDs at practice level. Qualitative data were obtained through focus groups.Results Out of 73 approached general practices, 55 implemented the HH programme. A total of 1082 patients agreed to participate in the HH study, of whom 64 patients were referred to the HH programme and 41 patients participated. Several barriers for participation were identified such as time investment, lack of risk perception, and being confident in changing lifestyle on their own. Important barriers for healthcare providers (HCPs) to refer a patient were time investment, lack of information to sufficiently inform patients, and preconceived notions regarding which patients the programme was suitable for.Conclusion This study has offered insights from a patient and HCP perspective regarding barriers and facilitators for implementation of the group-based lifestyle intervention programme. The identified barriers and facilitators, and the suggested improvements, can be used by others who wish to implement a similar programme. Show less
Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification... Show moreGlycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system. Show less
Brust, M.; Gebhardt, W.A.; Bruggen, S. van; Janssen, V.; Numans, M.E.; Kiefte-de Jong, J.C. 2023
AbstractObjectivePrevious research has shown that experiencing an acute cardiac event, such as a myocardial infarction (MI), can lead to lifestyle changes. This study aimed to explore the potential... Show moreAbstractObjectivePrevious research has shown that experiencing an acute cardiac event, such as a myocardial infarction (MI), can lead to lifestyle changes. This study aimed to explore the potential of a MI as a ‘teachable moment’ (TM) for positive lifestyle changes and to identify psychosocial sensemaking processes that facilitate or hinder the presence of a TM.MethodWe conducted semi-structured interviews with 14 patients who suffered their first MI and were hospitalized in a larger Dutch city. Participants were interviewed twice, respectively one and five months after their hospitalization. They were encouraged to explain how they experienced their MI and how this had affected their lifestyle. We used an Interpretative Phenomenological Analysis approach to the data collection and analysis.FindingsThe participants varied in their willingness to adopt a healthy lifestyle due to their MI. Most participants experienced their event as a TM for changing specific health behaviors, for example facilitated by reflecting on self-concept or social roles and by constructing and comprehending a personal narrative of their MI. Some participants struggled to follow through on their intentions to change their behavior, for example because of a negative attitude towards a healthy behavior or because they perceived it as incongruent to their identity. Only three participants maintained most former health behaviors, for example because they failed to acknowledge their MI as severe or because of earlier life events that elicited more blunted cognitive responses.ConclusionCardiac patients may experience a TM, which is the consequence of interrelated processes of psychosocial sensemaking. As this does not occur at a singular time point, we suggest using the term ‘teachable window’ rather than ‘moment’. Given these findings, there is a window of opportunity to provide continuous psychosocial and lifestyle support during and after hospitalization for acute cardiac events. Show less
Rakers, M.; Vijver, S. van de; Bossio, P.; Moens, N.; Rauws, M.; Orera, M.; ... ; Villalobos-Quesada, M. 2023
Background: eHealth offers opportunities to improve health and healthcare systems and overcome primary care challenges in low-resource settings (LRS). LRS has been typically associated with low-... Show moreBackground: eHealth offers opportunities to improve health and healthcare systems and overcome primary care challenges in low-resource settings (LRS). LRS has been typically associated with low- and middle-income countries (LMIC), but they can be found in high-income countries (HIC) when human, physical or financial resources are constrained. Adopting a concept of LRS that applies to LMIC and HIC can facilitate knowledge interchange between eHealth initiatives while improving healthcare provision for socioeconomically disadvantaged groups across the globe.Objectives: To outline the contributions and challenges of eHealth in low-resource primary care settings.Strategy: We adopt a socio-ecological understanding of LRS, making LRS relevant to LMIC and HIC. To assess the potential of eHealth in primary care settings, we discuss four case studies according to the WHO 'building blocks for strengthening healthcare systems'.Results and discussion: The case studies illustrate eHealth's potential to improve the provision of healthcare by i) improving the delivery of healthcare (using AI-generated chats); ii) supporting the workforce (using telemedicine platforms); iii) strengthening the healthcare information system (through patient-centred healthcare information systems), and iv) improving system-related elements of healthcare (through a mobile health financing platform). Nevertheless, we found that development and implementation are hindered by user-related, technical, financial, regulatory and evaluation challenges. We formulated six recommendations to help anticipate or overcome these challenges: 1) evaluate eHealth's appropriateness, 2) know the end users, 3) establish evaluation methods, 4) prioritise the human component, 5) profit from collaborations, ensure sustainable financing and local ownership, 6) and contextualise and evaluate the implementation strategies. Show less
Holzer, A.K.; Dreser, N.; Pallocca, G.; Mangerich, A.; Stacey, G.; Dipalo, M.; ... ; Leist, M. 2023
Every test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects,... Show moreEvery test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects, and mistakes introduced by operators, laboratory equipment, or materials used. Adherence to an SOP and comprehensive validation of the test method cannot guarantee that each test run produces data within the acceptable range of variability and with the precision and accuracy determined during the method validation. We illustrate here (part I) why controlling the validity of each test run is an important element of experimental design. The definition and application of acceptance criteria (AC) for the validity of test runs is important for the setup and use of test methods, particularly for the use of new approach methods (NAM) in toxicity testing. AC can be used for decision rules on how to handle data, e.g., to accept the data for further use (AC fulfilled) or to reject the data (AC not fulfilled). The adherence to AC has important requirements and consequences that may seem surprising at first sight: (i) AC depend on a test method's objectives, e.g., on the types/concentrations of chemicals tested, the regulatory context, the desired throughput; (ii) AC are applied and documented at each test run, while validation of a method (including the definition of AC) is only performed once; (iii) if AC are altered, then the set of data produced by a method can change. AC, if missing, are the blind spot of quality assurance: Test results may not be reliable and comparable. The establishment and uses of AC will be further detailed in part II of this series. Show less
Scheuplein, M.; Vermeulen, S.; van Harmelen, A.L.; Alink, L. 2023
It is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This... Show moreIt is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This chapter addresses one of the most societally pervasive consequences of child maltreatment which is known as the "cycle of victimization." This concept depicts the increased risk of maltreated individuals to victimize others later in life, both within and outside the family environment. To understand the architecture of this victimization cycle, the chapter further sheds light on neurocognitive mechanisms aiding different forms of victimization and the buffering role of social support that could help break the cycle of victimization. Advancing our understanding of these complex and interrelated mechanisms will ultimately facilitate the design and implementation of more targeted early treatments and (preventive) interventions and support a move toward a safer society. Show less
The role of Italian vernacular varieties in the history of communication in the Mediterranean world has only occasionally been investigated (see Baglioni 2010). In this research are brought to... Show moreThe role of Italian vernacular varieties in the history of communication in the Mediterranean world has only occasionally been investigated (see Baglioni 2010). In this research are brought to attention some letters exchanged between the States General of the United Provinces and the Ottoman Empire between the sixteenth and seventeenth centuries. They contribute to framing the spread of the Venetian variety as a lingua franca in diplomatic correspondence between the Mediterranean and Northern European worlds. Show less
BackgroundDiagnostics are increasingly shifting to patients’ home environment, facilitated by new digital technologies. Digital diagnostics (diagnostic services enabled by digital technologies) can... Show moreBackgroundDiagnostics are increasingly shifting to patients’ home environment, facilitated by new digital technologies. Digital diagnostics (diagnostic services enabled by digital technologies) can be a tool to better respond to the challenges faced by primary care systems while aligning with patients’ and healthcare professionals’ needs. However, it needs to be clarified how to determine the success of these interventions.ObjectivesWe aim to provide practical guidance to facilitate the adequate development and implementation of digital diagnostics.StrategyHere, we propose the quadruple aim (better patient experiences, health outcomes and professional satisfaction at lower costs) as a framework to determine the contribution of digital diagnostics in primary care. Using this framework, we critically analyse the advantages and challenges of digital diagnostics in primary care using scientific literature and relevant casuistry.ResultsTwo use cases address the development process and implementation in the Netherlands: a patient portal for reporting laboratory results and digital diagnostics as part of hybrid care, respectively. The third use case addresses digital diagnostics for sexually transmitted diseases from an international perspective.ConclusionsWe conclude that although evidence is gathering, the often-expected value of digital diagnostics needs adequate scientific evidence. We propose striving for evidence-based ‘responsible digital diagnostics’ (sustainable, ethically acceptable, and socially desirable digital diagnostics). Finally, we provide a set of conditions necessary to achieve it. The analysis and actionable guidance provided can improve the chance of success of digital diagnostics interventions and overall, the positive impact of this rapidly developing field. Show less
