Publications in 2021

Objectives: Studies in clinical settings showed a potential relationship between socioeconomic status (SES) and lifestyle factors with COVID-19, but it is still unknown whether this holds in the general population. In this study, we investigated the associations of SES with self- reported, tested and diagnosed COVID-19 status in the general population.

Design, setting, participants and outcome measures: Participants were 49 474 men and women (46±12 years) residing in the Northern Netherlands from the Lifelines cohort study. SES indicators and lifestyle factors (i.e., smoking status, physical activity, alcohol intake, diet quality, sleep time and TV watching time) were assessed by questionnaire from the Lifelines Biobank. Self- reported, tested and diagnosed COVID-19 status was obtained from the Lifelines COVID-19 questionnaire.

Results: There were 4711 participants who self- reported having had a COVID-19 infection, 2883 participants tested for COVID-19, and 123 positive cases were diagnosed in this study population. After adjustment for age, sex, lifestyle factors, body mass index and ethnicity, we found that participants with low education or low income were less likely to self- report a COVID-19 infection (OR [95% CI]: low education 0.78 [0.71 to 0.86]; low income 0.86 [0.79 to 0.93]) and be tested for COVID-19 (OR [95% CI]: low education 0.58 [0.52 to 0.66]; low income 0.86 [0.78 to 0.95]) compared with high education or high income groups, respectively.

Conclusion: Our findings suggest that the low SES group was the most vulnerable population to self- reported and tested COVID-19 status in the general population.

Poor prognosis caused by type 2 diabetes mellitus (T2DM) in women with breast cancer is conferred, while the association between T2DM and breast tumor aggressiveness is still a matter of debate. This study aimed to clarify the differences in breast cancer characteristics, including stage, size, lymph node status, grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2), between patients with and without pre-existing T2DM. PubMed, Embase, and Web of Science were searched for studies from 1 January 2010 to 2 July 2021. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by using a random effects model. T2DM was significantly associated with tumor stages III/IV versus cancers in situ and stages I/II (pooled ORs (pOR), 95% CI: 1.19; 1.04–1.36, p = 0.012), tumor size >20 versus 20 mm (pOR, 95% CI: 1.18; 1.04–1.35, p = 0.013), and lymph node invasion versus no involvement (pOR, 95% CI: 1.26; 1.05–1.51, p = 0.013). These findings suggest that women with T2DM are at a higher risk of late-stage tumors, large tumor sizes, and invasive lymph nodes at breast cancer diagnosis.

In this study, we estimated the benefits of rotavirus vaccination for infants had the rotavirus vaccine been introduced in the Netherlands as of its market authorization in 2006. An age-structured, deterministic cohort model was developed to simulate different birth cohorts over a period of 15 years from 2006 until 2021, comparing both universal and targeted high-risk group vaccination to no vaccination. Different scenarios for the duration of protection (5 or 7 years) and herd immunity (only for universal vaccination) were analyzed. All birth cohorts together included 2.6 million infants, of which 7.9% were high-risk individuals, and an additional 13.2 million children between 1-15 years born prior to the first cohort in 2006. The costs and health outcomes associated with rotavirus vaccination were calculated per model scenario and discounted at 4% and 1.5%, respectively. Our analysis reveals that, had rotavirus vaccination been implemented in 2006, it would have prevented 356,800 (51% decrease) and 32,200 (5% decrease) cases of rotavirus gastroenteritis after universal and targeted vaccination, respectively. Over the last 15 years, this would have led to significant avoided costs and quality-adjusted life year losses for either vaccination strategy with the most favorable outcomes for universal vaccination. Clearly, an opportunity has been lost.

Objectives: As of 2019, quadrivalent influenza vaccine (QIV) has replaced trivalent influenza vaccine (TIV) in the national immunization program in The Netherlands. Target groups are individuals of 601 years of age and those with chronic diseases. The objective was to estimate the incremental break-even price of QIV over TIV at a threshold of EUR20.000 per quality-adjusted life-year (QALY).

Methods: An age-structured compartmental dynamic model was adapted for The Netherlands to assess health outcomes and associated costs of vaccinating all individuals at higher risk for influenza with QIV instead of TIV over the seasons 2010 to 2018. Influenza incidence rates were derived from a global database. Other parameters (probabilities, QALYs and costs) were extracted from the literature and applied according to Dutch guidelines. A threshold of EUR20.000 per QALY was applied to estimate the incremental break-even prices of QIV versus TIV. Sensitivity analyses were performed to test the robustness of the model outcomes.

Results: Retrospectively, vaccination with QIV instead of TIV could have prevented on average 9500 symptomatic influenza cases, 2130 outpatient visits, 84 hospitalizations, and 38 deaths per year over the seasons 2010 to 2018. This translates into 385 QALYs and 398 life-years potentially gained. On average, totals of EUR431.527 direct and EUR2.388.810 indirect costs could have been saved each year.

Conclusion: Using QIV over TIV during the influenza seasons 2010 to 2018 would have been cost-effective at an incremental price of maximally EUR3.81 (95% confidence interval, EUR3.26-4.31). Sensitivity analysis showed consistent findings on the incremental break-even price in the same range.

Background: HER2+ tumors make up approximately 20% of MBCs. The survival outcomes for HER2+ MBC patients improved significantly in the last decade due to the development of HER2-targeted therapies. The objective of this SLR was to assess recent evidence on the burden of HER2+ MBC.

Methods: A SLR was conducted in MEDLINE and EMBASE databases (2010-2020) and congress abstract repositories (2018-2020). The search adhered to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 8,115 records were identified, of which 6,549 were retrieved upon deduplication. Two reviewers independently screened titles and abstracts for eligibility. Fulltext review of 571 articles was then carried out.

Results: 260 studies met the inclusion criteria. Seven sources of which compared HER2+ mBC patients to the general and BC populations reporting impaired health utility scores and moderate or worse health status. This was assessed using a variety of tools, such as EQ-5D-5L, FACT-B and EORTC QLQ-C30. In addition to lower Quality of Life (QoL), the disease is associated with impairment of work- and daily activity, negative body image perception, and mental disorders. The symptoms, comorbidities and treatment adverse events most frequently reported by HER2+ mBC patients include tiredness, decreased sexual interest, lack of energy, sore muscles, worry, difficulty sleeping and joint pain. Due to the longer treatment duration and high treatment costs of anti-HER2 treatments, HER2+ MBC leads to greater costs than other types of mBC. In Europe, overall-per-patient costs of HER2+ mBC per patient were V235,238-V269,749, of which V37,431-53,950 were annual treatment costs. Costs are primarily driven by treatment and hospitalization costs, and accumulatively increase by line of treatment.

Conclusions: With improvements in disease management being made in recent years, the SLR demonstrated that a substantial burden of HER2+ MBC on patients’ QoL and on the healthcare systems still exists, highlighting the need for more cost-effective treatment options.

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart – leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using “rule-in” examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the f ield and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

Aim: To externally validate the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2) by comparing the predicted and observed outcomes in two European population-based cohorts of people with type 2 diabetes.

Materials and methods: We used data from the Casale Monferrato Survey (CMS; n = 1931) and a subgroup of the Hoorn Diabetes Care System (DCS) cohort (n = 5188). The following outcomes were analysed: all-cause mortality, myocardial infarction (MI), ischaemic heart disease (IHD), stroke, and congestive heart failure (CHF). Model performance was assessed by comparing predictions with observed cumulative incidences in each cohort during follow-up.

Results: All-cause mortality was overestimated by the UKPDS-OM2 in both the cohorts, with a bias of 0.05 in the CMS and 0.12 in the DCS at 10 years of follow-up. For MI, predictions were consistently higher than observed incidence over the entire follow-up in both cohorts (10 years bias 0.07 for CMS and 0.10 for DCS). The model performed well for stroke and IHD outcomes in both cohorts. CHF incidence was predicted well for the DCS (5 years bias -0.001), but underestimated for the CMS cohort.

Conclusions: The UKPDS-OM2 consistently overpredicted the risk of mortality and MI in both cohorts during follow-up. Period effects may partially explain the differences. Results indicate that transferability is not satisfactory for all outcomes, and new or adjusted risk equations may be needed before applying the model to the Italian or Dutch settings.

Introduction: Progression of amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) is a clinical event with highly variable progression rates varying from 10–15% up to 30–34%. Functional connectivity (FC), the temporal similarity between spatially remote neurophysiological events, has previously been reported to differ between aMCI patients who progress to AD (pMCI) and those who do not (i.e., remain stable; sMCI). However, these reports had a short-term follow-up and do not provide insight into long-term AD progression.

Methods: Seventy-nine participants with a baseline and 78 with a 12-month, 51 with a 24-month, and 22 with a +48-month follow-up resting-state fMRI with aMCI diagnosis from the Alzheimer’s Disease Neuroimaging Initiative database were included. FC was assessed using the CONN toolbox. Local correlation and group independent component analysis were utilized to compare regional functional coupling and between-network FC, respectively, between sMCI and pMCI groups. Two-sample t tests were used to test for statistically significant differences between groups, and paired t-tests were used to assess cognitive changes over time.

Results: All participants (i.e., 66 sMCI and 19 pMCI) had a baseline and a year follow-up fMRI scan. Progression from aMCI to AD occurred in 19 patients (10 at 12 months, 5 at 24 months, and 4 at >48 months), while 73 MCI patients remained cognitively stable (sMCI). The pMCI and sMCI cognitive profiles were different. More between-network FC than regional functional coupling differences were present between sMCI and pMCI patients. Activation in the salience network (SN) and the default mode network (DMN) was consistently different between sMCI and pMCI patients across time.

Discussion: sMCI and pMCI patients have different cognitive and FC profiles. Only pMCI patients showed cognitive differences across time. The DMN and SN showed local correlation and between-network FC differences between the sMCI and pMCI patient groups at multiple moments in time.

Objective: To explore changes in resting-state networks in patients with jerky and tremulous functional movement disorders (JT-FMD).

Methods: Resting-state functional magnetic resonance imaging data from seventeen patients with JT-FMD and seventeen age-, sex-, and education-matched healthy controls (HC) were investigated. Independent component analysis was used to examine the central executive network (CEN), salience network, and default mode network (DMN). Frequency distribution of network signal fluctuations and intra- and internetwork functional connectivity were investigated. Symptom severity was measured using the Clinical Global Impression-Severity scale. Beck Depression Inventory and Beck Anxiety Inventory scores were collected to measure depression and anxiety in FMD, respectively.

Results: Compared with HC, patients with JT-FMD had significantly decreased power of lower range (0.01–0.10Hz) frequency fluctuations in a precuneus and posterior cingulate cortex component of the DMN and in the dorsal attention network (DAN) component of the CEN (false discovery rate-corrected p<0.05). No significant group differences were found for intra- and internetwork functional connectivity. In patients with JT-FMD, symptom severity was not significantly correlated with network measures. Depression scores were weakly correlated with intranetwork functional connectivity in the medial prefrontal cortex, while anxiety was not found to be related to network connectivity.

Conclusions: Given the changes in the posterodorsal components of the DMN and DAN, we postulate that the JT-FMD-related functional alterations found in these regions could provide support for the concept that particularly attentional dysregulation is a fundamental disturbance in these patients.

Background: Schizophrenia Spectrum Disorder (SSD) is characterized by its chronic, episodic nature. The clear definition of such episodes is essential for various clinical and research purposes. Most current definitions of episodes in SSD are based on either hospitalizations or on symptom scales. Both have drawbacks; symptom scales are measured infrequently, while hospitalization rates are often affected by policy. This study presents an approach for defining episodes in healthcare data that does not suffer such drawbacks.

Methods: Healthcare use of 13,155 SSD patients in the Northern Netherlands with up to 12 years of follow-up was available. Patient-level structural changes in the trend of healthcare use costs were determined using Exponentially Weighted Moving Average (EWMA) control charts. Control charts restart with updated parameters after a detected structural change. Episodes were defined using these structural changes. The resulting episodes were validated by investigating their association with the Global Assessment of Functioning (GAF) scale.

Results: The mean number of episodes was 0.61 (sd: 0.60) per patient per year. For the sub-group without hospitalizations this was 0.51 (sd: 0.71). Average episode duration of the sub-group (147 days, sd: 309.4) was similar to that of the full sample (150 days, sd: 305.5). A significant inverse association was identified between GAF scores and the episode-state indicator.

Conclusions: The repeated application of EWMA control charts based on healthcare-intensity is a feasible and promising tool for quantifying patient-level healthcare episodes. The validation using GAF scores indicates that our episode indicator is associated with lower levels of global functioning. Results for individuals without hospitalizations indicate that the method is robust with regard to changes in healthcare policy.

Aims: Rifaximin-a as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-a remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-a as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer’s perspective.

Materials and methods: A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness.

Results: Treating eligible HE patients with rifaximin-a in addition to lactulose saves e4,487 and costse249 per patient over a 5-year period compared with lactulose monotherapy from hospital and health-care payer’s perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligiblepatients are currently being treated with rifaximin-a. Optimizing rifaximin-a use by treating all eligiblepatients with the rifaximin-a þ lactulose could save more than 3,000 hospital admissions, almost15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treat-ment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from aDutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer’s perspective.

Conclusions: Next to a clinical perspective, also from an economic perspective, wider prescription ofrifaximin-a adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer’s perspective, costs increase with addition of rifaximin-a due to relative better survival causing relatively higher drug and liver transplantation-related costs.

Purpose: Cognitive biases and factors affecting decision making in critical care can potentially lead to life threatening errors. We aimed to examine the existing evidence on the influence of cognitive biases and factors on decision making in critical care.

Materials and methods: We conducted a scoping review by searching MEDLINE for articles from 2004 to November 2020. We included studies conducted in physicians that described cognitive biases or factors associated with decision making. During the study process we decided on the method to summarize the evidence, and based on the obtained studies a descriptive summary of findings was the best fit.

Results: Thirty heterogenous studies were included. Four main biases or factors were observed, e.g. cognitive biases, personal factors, environmental factors, and patient factors. Six (20%) studies reported biases associated with decision making comprising omission-, status quo-, implicit-, explicit-, outcome-, and overconfidence bias. Nineteen (63%) studies described personal factors, twenty-two (73%) studies described environmental factors, and sixteen (53%) studies described patient factors.

Conclusions: The current evidence on cognitive biases and factors is heterogenous, but shows they influence clinical decision. Future studies should investigate the prevalence of cognitive biases and factors in clinical practice and their impact on clinical outcomes.