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OBJECTIVE: To explore whether a mentalization-based communication training for pharmacy staff impacts their ability to elicit and recognize patients' implicit and explicit medication related needs and concerns.METHODS: A single-arm intervention pilot study was conducted, in which pre-post video-recordings of pharmacy counter-conversations on dispensed-medication (N = 50 and N = 34, respectively; pharmacy staff: N = 22) were coded. Outcome measures included: detecting needs and concerns, and implicitly and explicitly eliciting and recognizing them. Descriptive statistics and a multi-level logistic regression were conducted. Excerpts of videos with needs or concerns were analyzed thematically on mentalizing attitude aspects.RESULTS: Indications show that patients more often express their concerns in an explicit way post-measurement, just as pharmacy staffs' explicit recognition and elicitation of needs and concerns. This was not seen for patients' needs. No statistically significant differences were found for determinants for detecting needs or concerns (i.e., measurement-, professional-type, or interaction). Differences in mentalizing attitude were observed between pre-post-measurements, e.g., more attention for patients.CONCLUSION: This mentalizing training shows the potential of mentalizing to improve pharmacy staff members' explicit elicitation and recognition of patients' medication-related needs and concerns.PRACTICE IMPLICATIONS: The training seems promising for improving patient-oriented communication skills in pharmacy staff. Future studies should confirm this result.

Background: Sudden cardiac death is responsible for 10% to 20% of all deaths in Europe. The current study investigates how well the risk of sudden cardiac death can be predicted. To this end, we validated a previously developed prediction model for sudden cardiac death from the Atherosclerosis Risk in Communities study (USA). Methods: Data from participants of the Copenhagen City Heart Study (CCHS) (n=9988) was used to externally validate the previously developed prediction model for sudden cardiac death. The model's performance was assessed through discrimination (C-statistic) and calibration by the Hosmer-Lemeshow goodness-of-fit (HL) statistics suited for censored data and visual inspection of calibration plots. Additional validation was performed using data from the Hoorn Study (N=2045), employing the same methods. Results: During ten years of follow-up of CCHS participants (mean age: 58.7 years, 56.2% women), 425 experienced SCD (4.2%). The prediction model showed good discrimination for sudden cardiac death risk (C-statistic: 0.81, 95% CI: 0.79-0.83). Calibration was robust (HL statistic: P=0.8). Visual inspection of the calibration plot showed that the calibration could be improved. Sensitivity was 89.8%, and specificity was 60.6%. The positive and negative predictive values were 10.1% and 99.2%. Model performance was similar in the Hoorn Study (C-statistic: 0.81, 95% CI: 0.77-0.85 and the HL statistic: 1.00). Conclusion: Our study showed that the previously developed prediction model in North American adults performs equally well in identifying those at risk for sudden cardiac death in a general North-West European population. However, the positive predictive value is low.

The objective of the study was to gain an insight into the perceptions and experiences of patients with rheumatoid arthritis and a high cardiovascular disease risk (CVD-RA) when undergoing an exercise intervention aimed at improving their cardiorespiratory fitness. This qualitative study was part of a pilot study, which investigated the effects of an exercise intervention on cardiorespiratory fitness in patients with CVD-RA. Six patients were invited to participate in face-to-face semi-structured interviews. We invited patients who completed the exercise intervention as well as patients who withdrew from the exercise intervention. The interviews were analyzed according to the method of thematic analysis. Six patients were interviewed, of whom four patients completed and two patients discontinued the exercise intervention. The mean (SD) age was 58 (9.7) years, the median disease duration was 10 years, and five patients were female. The analyses revealed seven themes that provided insight into perceptions and experiences: (1) ability to understand reasons for actions; (2) the need to be seen; (3) reaching their maximum effort; (4) experiencing their limits; (5) wanting personalized exercise therapy; (6) happy to be physically active; (7) benefits of exercise. Patients perceived that they were able to perform a cardiopulmonary exercise test with maximum effort and achieved the prescribed intensity of the exercise intervention. They also experienced an improvement in their physical activity by incorporating physical activity in their daily live. Overarching principles that re-occurred in the themes were: the need to be viewed as a person and the importance of feeling safe.

Purpose: To investigate the agreement between an online nurse-assisted eye-screening tool and reference tests in older adults receiving home healthcare and to collect user experiences. Methods: Older adults (65+) receiving home healthcare were included. Home healthcare nurses assisted in administering the eye-screening tool at participants' homes. Approximately 2 weeks later, a researcher administered reference tests at participants' homes. Experiences from participants and home healthcare nurses were collected. Agreement in outcomes (distance and near visual acuity, with the latter being measured using two different optotypes, and macular problems) between the eye-screening tool and reference clinical testing was compared. A difference of less than ±0.15 logMAR was considered acceptable. Results: A total of 40 participants were included. Here, we describe the results for the right eye; results for the left eye were similar. The mean difference between the eye-screening tool and reference tests for distance visual acuity was 0.02 logMAR. The mean difference between the eye-screening tool and reference tests using two different optotypes for near visual acuity was 0.06 and 0.03 logMAR, respectively. The majority of the individual data points were within the ±0.15 logMAR threshold (75%, 51% and 58%, respectively). The agreement between tests for macular problems was 75%. Participants and home healthcare nurses were generally satisfied with the eye-screening tool, although remarks for further improvements were made. Conclusions: The eye-screening tool is promising for nurse-assisted eye screening in older adults receiving home healthcare, with the mostly satisfactory agreement. After implementing the eye-screening tool in practice, cost-effectiveness needs to be investigated.

Objective: Low dietary guideline adherence is persistent, but there is limited understanding of how individuals with varying socio-economic backgrounds reach a certain dietary intake. We investigated how quantitative and qualitative data on dietary guidelines adherence correspond and complement each other, to what extent determinants of guideline adherence in quantitative data reflect findings on determinants derived from qualitative data and which of these determinants emerged as interdependent in the qualitative data. Design: This mixed-methods study used quantitative questionnaire data (n 1492) and qualitative data collected via semi-structured telephone interviews (n 24). Quantitative data on determinants and their association with total guideline adherence (scored 0–150) were assessed through linear regression. Directed content analysis was used for qualitative data. Setting: Dutch urban areas. Participants: Adults aged 18–65 years. Results: A range of determinants emerged from both data sources, for example higher levels of cognitive restraint (β 5·6, 95 % CI 4·2, 7·1), habit strength of vegetables (β 4·0, 95 % CI 3·3, 4·7) and cooking skills (β 4·7, 95 % CI 3·5, 5·9), were associated with higher adherence. Qualitative data additionally suggested the influence of food prices, strong dietary habits and the social aspect of eating, and for the determinants cognitive restraint, habit strength related to vegetables, food prices and home cooking, some variation between interviewees with varying socio-economic backgrounds emerged in how these determinants affected guideline adherence. Conclusions: This mixed-methods exploration provides a richer understanding of why adults with varying socio-economic backgrounds do or do not adhere to dietary guidelines. Results can guide future interventions promoting healthy diets across populations.

Introduction: Conflicting evidence exists concerning whether having sarcopenic obesity has additive mortality risk over having only sarcopenia or obesity. We examined the independent and combined associations of obesity and probable sarcopenia with all-cause mortality. Methods: The pooled analysis included three large, harmonized datasets (Health 2000 Survey; Health, Aging and Body Composition Study; Longitudinal Aging Study Amsterdam) with mortality follow-up data on individuals aged 70 years and over at baseline (n = 4,612). Obesity indicators included body mass index and waist circumference, and probable sarcopenia was defined based on grip strength. The mixed effects Cox model was used for statistical analyses, adjusting for age, sex, marital status, education, race, physical activity, alcohol consumption, smoking, and baseline diseases. Results: Risk of death increased for those having probable sarcopenia only (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.39–1.85) or probable sarcopenia with obesity (HR: 1.36, 95% CI: 1.13–1.64) but not for the obese-only group (HR: 0.92, 95% CI: 0.85–1.01), when compared to non-obese non-sarcopenic individuals. The results were similar regardless of adjustments for covariates or different obesity criteria applied. Conclusion: Probable sarcopenia, whether combined with obesity or not, is associated with increased mortality. Obesity did not increase mortality among older adults. Maintaining muscle strength and identifying older adults at risk of sarcopenia is important for the prevention of premature mortality.

Objectives: To elicit the relative importance of the benefits and harms of colorectal cancer (CRC) screening among potential screening participants in the Dutch population. Methods: In a consensus meeting with 11 experts, risk reduction of CRC and CRC deaths (benefits) and complications from colonoscopy, stress of receiving positive fecal immunological test (FIT) results, as well as false-positive and false-negative FIT results (harms) were selected as determinant end points to consider during decision making. We conducted an online best-worst scaling survey among adults aged 55 to 75 years from the Dutch Health Care Consumer Panel of The Netherlands Institute for Health Services Research to elicit preference values for these outcomes. The preference values were estimated using conditional logit regression. Results: Of 265 participants, 234 (89%) had ever participated in CRC screening. Compared with the stress of receiving a positive FIT result, the outcome perceived most important was the risk of CRC death (odds ratio [OR] 4.5; 95% confidence interval [CI] 3.9-5.1), followed by risk of CRC (OR 4.1; 95% CI 3.6-4.7), a false-negative FIT result (OR 3.1; 95% CI 2.7-3.5), colonoscopy complications (OR 1.6; 95% CI 1.4-1.8), and a false-positive FIT result (OR 1.4; 95% CI 1.3-1.6). The magnitude of these differences in perceived importance varied according to age, educational level, ethnic background, and whether the individual had previously participated in CRC screening. Conclusion: Dutch men and women eligible for FIT-based CRC screening perceive the benefits of screening to be more important than the harms.

Objectives: To illustrate in-depth validation of prediction models developed on multicenter data. Methods: For each hospital in a multicenter registry, we evaluated predictive performance of a 30-day mortality prediction model for transcatheter aortic valve implantation (TAVI) using the Netherlands heart registration (NHR) dataset. We measured discrimination and calibration per hospital in a leave-center-out analysis (LCOA). Meta-analysis was used to calculate I2 values per performance metric from the LCOA and to compute mean and confidence interval (CI) estimates. Case mix differences between studies were inspected using the framework of Debray et al. for understanding external validation. We also aimed to discover subgroups (SGs) with high model prediction error (PE) and their distribution over the centers. Results: We studied 16 hospitals with 11,599 TAVI patients with an early mortality of 3.7%. The models’ area under the curve (AUCs) had a wide range between hospitals from 0.59 to 0.79, and miscalibration occurred in seven hospitals. Mean AUC from meta-analysis was 0.68 (95% CI 0.65-0.70). I2 values were 0%, 74%, and 0% for AUC, calibration intercept and slope, respectively. Between-hospital case-mix differences were substantial, and model transportability was low. One SG was discovered with marked global PE and was associated with poor performance on validation centers. Conclusion: The illustrated combination of approaches provides useful insights to inspect multicenter-based prediction models, and it exposes their limitations in transportability and performance variability when applied to different populations.

Background Reducing health inequalities is a challenge for policymakers and civil society. A multisectoral and multilevel approach is most promising to reduce those inequalities. Previous research showed what key elements of Zwolle Healthy City, an integrated community-based approach aimed at reducing socioeconomic health inequalities, are. To fully understand approaches that are complex and context dependent, questions as ‘how does the intervention work’ and ‘in what context does it work’ are just as important as ‘what works’. The current study aimed to identify mechanisms and contextual factors associated with the key elements of Zwolle Healthy City, using a realist evaluation perspective. Methods Transcripts of semi-structured interviews with a wide range of local professionals were used (n = 29). Following realist evaluation logic in the analysis of this primary data, context-mechanism-outcome configurations were identified and thereafter discussed with experts (n = 5). Results How mechanisms (M) in certain contexts (C) were of influence on the key elements (O) of the Zwolle Healthy City approach are described. For example, how, in the context of the responsible aldermen embracing the approach (C), regular meetings with the aldermen (M) increased support for the approach among involved professionals (O). Or, how, in the context of available financial resources (C), assigning a program manager (M) contributed positively to coordination and communication (O). All 36 context-mechanism-outcome configurations can be found in the repository. Conclusion This study showed what mechanisms and contextual factors are associated with the key elements of Zwolle Healthy City. By applying realist evaluation logic in the analysis of primary qualitative data we were able to disentangle the complexity of processes of this whole system approach and show this complexity in a structured manner. Also, by describing the context in which the Zwolle Healthy City approach is implemented, we contribute to the transferability of this approach across different contexts.

BACKGROUND AND OBJECTIVES: Case 2 best-worst scaling (BWS-2) is an increasingly popular method to elicit patient preferences. Because BWS-2 potentially has a lower cognitive burden compared with discrete choice experiments, the aim of this study was to compare treatment preference weights and relative importance scores.METHODS: Patients with neuromuscular diseases completed an online survey at two different moments in time, completing one method per occasion. Patients were randomly assigned to either first a discrete choice experiment or BWS-2. Attributes included: muscle strength, energy endurance, balance, cognition, chance of blurry vision, and chance of liver damage. Multinomial logit was used to calculate overall relative importance scores and latent class logit was used to estimate heterogeneous preference weights and to calculate the relative importance scores of the attributes for each latent class.RESULTS: A total of 140 patients were included for analyses. Overall relative importance scores showed differences in attribute importance rankings between a discrete choice experiment and BWS-2. Latent class analyses indicated three latent classes for both methods, with a specific class in both the discrete choice experiment and BWS-2 in which (avoiding) liver damage was the most important attribute. Ex-post analyses showed that classes differed in sex, age, level of education, and disease status. The discrete choice experiment was easier to understand compared with BWS-2.CONCLUSIONS: This study showed that using a discrete choice experiment and BWS-2 leads to different outcomes, both in preference weights as well as in relative importance scores, which might have been caused by the different framing of risks in BWS-2. However, a latent class analysis revealed similar latent classes between methods. Careful consideration about method selection is required, while keeping the specific decision context in mind and pilot testing the methods.

Sympathovagal balance is important in the pathogenesis of hypertension and independently associated with mortality. We evaluated the value of automated analysis of cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) and its relationship with clinical covariates in 13,326 participants from the multi-ethnic HELIUS study. Finger blood pressure (BP) was continuously recorded, from which xBRS, standard deviation of normal-to-normal intervals (SDNN), and squared root of mean squared successive difference between normal-to-normal intervals (RMSDD) were determined. A subset of 3356 recordings > 300 s was used to derive the minimally required duration by comparing shortened to complete recordings, defined as intraclass correlation (ICC) > 0.90. For xBRS and SDNN, 120 s and 180 s were required (ICC 0.93); for RMSDD, 60 s (ICC 0.94) was sufficient. We included 10,252 participants (median age 46 years, 54% women) with a recording > 180 s for the regression. xBRS, SDNN, and RMSDD decreased linearly up to 50 years of age. For xBRS, there was a signification interaction with sex, with for every 10 years a decrease of 4.3 ms/mmHg (95%CI 4.0–4.6) for men and 5.9 ms/mmHg (95%CI 5.6–6.1) for women. Using splines, we observed sex-dependent nonlinearities in the relation with BP, waist-to-hip-ratio, and body mass index. Future studies can help unravel the dynamics of these relations and assess their predictive value. Graphical Abstract Panel 1 depicts automatic analysis and filtering of finger BP recordings, panel 2 depicts computation of xBRS from interpolated beat to beat data of systolic BP and interbeat interval, and (IBI) SDNN and RMSDD are computed directly from the filtered IBI dataset. Panel 3 depicts the results of large-scale analysis and relation of xBRS with age, sex, blood pressure and body mass index.

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Background Most patients with atherosclerotic cardiovascular disease remain at (very) high risk for recurrent events due to suboptimal risk factor control. Aims This study aimed to quantify the potential of maximal risk factor treatment on 10-year and lifetime risk of recurrent atherosclerotic cardiovascular events in patients 1 year after a coronary event. Methods and results Pooled data from six studies are as follows: RESPONSE 1, RESPONSE 2, OPTICARE, EUROASPIRE IV, EUROASPIRE V, and HELIUS. Patients aged ≥45 years at ≥6 months after coronary event were included. The SMART-REACH score was used to estimate 10-year and lifetime risk of recurrent atherosclerotic cardiovascular events with current treatment and potential risk reduction and gains in event-free years with maximal treatment (lifestyle and pharmacological). In 3230 atherosclerotic cardiovascular disease patients (24% women), at median interquartile range (IQR) 1.1 years (1.0–1.8) after index event, 10-year risk was median (IQR) 20% (15–27%) and lifetime risk 54% (47–63%). Whereas 70% used conventional medication, 82% had ≥1 drug-modifiable risk factor not on target. Furthermore, 91% had ≥1 lifestyle-related risk factor not on target. Maximizing therapy was associated with a potential reduction of median (IQR) 10-year risk to 6% (4–8%) and of lifetime risk to 20% (15–27%) and a median (IQR) gain of 7.3 (5.4–10.4) atherosclerotic cardiovascular disease event-free years. Conclusions Amongst patients with atherosclerotic cardiovascular disease, maximizing current, guideline-based preventive therapy has the potential to mitigate a large part of their risk of recurrent events and to add a clinically important number of event-free years to their lifetime.

Objectives: Preventive measures against COVID-19 are essential for pregnant women. Pregnant women are particularly vulnerable to emerging infectious pathogens due to alterations in their physiology. We aimed to determine the optimum timing of vaccination to protect pregnant women and their neonates from COVID-19. Methods: A prospective observational longitudinal cohort study in pregnant women who received COVID-19 vaccination. We collected blood samples to evaluate levels of antispike, receptor binding domain and nucleocapsid antibodies against SARS-CoV-2 before vaccination and 15 days after the first and second vaccination. We determined the neutralizing antibodies from mother-infant dyads in maternal and umbilical cord blood at birth. If available, immunoglobulin A was measured in human milk. Results: We included 178 pregnant women. Median antispike immunoglobulin G levels increased significantly from 1.8 to 5431 binding antibody units/ml and receptor binding domain from 6 to 4466 binding antibody units/ml. Virus neutralization showed similar results between different weeks of gestation at vaccination (P >0.3). Conclusion: We advise vaccination in the early second trimester of pregnancy for the optimum balance between the maternal antibody response and placental antibody transfer to the neonate.

Urbanization and inequalities are two of the major policy themes of our time, intersecting in large cities where social and economic inequalities are particularly pronounced. Large scale street-level images are a source of city-wide visual information and allow for comparative analyses of multiple cities. Computer vision methods based on deep learning applied to street images have been shown to successfully measure inequalities in socioeconomic and environmental features, yet existing work has been within specific geographies and have not looked at how visual environments compare across different cities and countries. In this study, we aim to apply existing methods to understand whether, and to what extent, poor and wealthy groups live in visually similar neighborhoods across cities and countries. We present novel insights on similarity of neighborhoods using street-level images and deep learning methods. We analyzed 7.2 million images from 12 cities in five high-income countries, home to more than 85 million people: Auckland (New Zealand), Sydney (Australia), Toronto and Vancouver (Canada), Atlanta, Boston, Chicago, Los Angeles, New York, San Francisco, and Washington D.C. (United States of America), and London (United Kingdom). Visual features associated with neighborhood disadvantage are more distinct and unique to each city than those associated with affluence. For example, from what is visible from street images, high density poor neighborhoods located near the city center (e.g., in London) are visually distinct from poor suburban neighborhoods characterized by lower density and lower accessibility (e.g., in Atlanta). This suggests that differences between two cities is also driven by historical factors, policies, and local geography. Our results also have implications for image-based measures of inequality in cities especially when trained on data from cities that are visually distinct from target cities. We showed that these are more prone to errors for disadvantaged areas especially when transferring across cities, suggesting more attention needs to be paid to improving methods for capturing heterogeneity in poor environment across cities around the world.

Background Recruiting participants for lifestyle programmes is known to be challenging. Insights into recruitment strategies, enrolment rates and costs are valuable but rarely reported. We provide insight into the costs and results of used recruitment strategies, baseline characteristics and feasibility of at-home cardiometabolic measurements as part of the Supreme Nudge trial investigating healthy lifestyle behaviours. This trial was conducted during the COVID-19 pandemic, requiring a largely remote data collection approach. Potential sociodemographic differences were explored between participants recruited through various strategies and for at-home measurement completion rates. Methods Participants were recruited from socially disadvantaged areas around participating study supermarkets (n = 12 supermarkets) across the Netherlands, aged 30–80 years, and regular shoppers of the participating supermarkets. Recruitment strategies, costs and yields were logged, together with completion rates of at-home measurements of cardiometabolic markers. Descriptive statistics are reported on recruitment yield per used method and baseline characteristics. We used linear and logistic multilevel models to assess the potential sociodemographic differences. Results Of 783 recruited, 602 were eligible to participate, and 421 completed informed consent. Most included participants were recruited via letters/flyers at home (75%), but this strategy was very costly per included participant (89 Euros). Of paid strategies, supermarket flyers were the cheapest (12 Euros) and the least time-invasive (n = 391) were on average 57.6 (SD 11.0) years, 72% were female and 41% had high educational attainment, and they often completed the at-home measurements successfully (lipid profile 88%, HbA1c 94%, waist circumference 99%). Multilevel models suggested that males tended to be recruited more often via word-of-mouth (ORfemales 0.51 (95%CI 0.22; 1.21)). Those who failed the first attempt at completing the at-home blood measurement were older (β 3.89 years (95% CI 1.28; 6.49), whilst the non-completers of the HbA1c (β − 8.92 years (95% CI − 13.62; − 4.28)) and LDL (β − 3.19 years (95% CI − 6.53; 0.09)) were younger. Conclusions Supermarket flyers were the most cost-effective paid strategy, whereas mailings to home addresses recruited the most participants but were very costly. At-home cardiometabolic measurements were feasible and may be useful in geographically widespread groups or when face to face contact is not possible. Trial registration Dutch Trial Register ID NL7064, 30 May 2018, https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7302

Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease.

Background Current literature reports a gap between development of effective interventions to promote physical activity and the systematic uptake into real-world settings. Factors relating to implementation and scale-up of physical activity interventions have been examined, however the perspectives of multiple stakeholders from different domains are not well researched. The purpose of this study was to examine the perceived factors related to physical activity intervention implementation and scale-up in different domains from different stakeholders on the island of Ireland. Methods Practitioners, researchers, funders and policy makers in Ireland were invited to take part in a semi-structured interview exploring factors related to the implementation and scale-up of eleven different physical activity interventions. A thematic analysis was conducted to identify factors related to the implementation and scale-up of the included interventions. The data collection and analysis were guided by the Consolidated Framework for Implementation Research. Results Thirty-eight participants took part in the interviews which identified factors related to 1) intervention planning and practical considerations; 2) organisational structures, staffing and resources related to delivery; 3) reflection, evaluation and updating of the intervention; and 4) practical consideration related to scale-up. Furthermore, participants referred to the ongoing commitment, engagement, and support needed throughout the implementation process. Conclusions Future research and practice needs to consider how different factors are experienced at different implementation stages and by the different stakeholder groups involved. The findings highlight multiple inter-related factors that influence the implementation and scale-up of physical activity interventions, but also identifies many strategies that can be utilised to aid future successes.

Background Physical activity (PA) levels might be a simple overall physical function indicator of recovery in acutely hospitalized older adults; however it is unknown which amount and level of PA is associated with recovery. Our objective was to evaluate the amount and level of post discharge PA and its optimum cut-off values associated with recovery among acutely hospitalized older adults and stratified for frailty. Methods We performed a prospective observational cohort study including acutely hospitalized older adults (≥ 70 years). Frailty was assessed using Fried’s criteria. PA was assessed using Fitbit up to one week post discharge and quantified in steps and minutes light, moderate or higher intensity. The primary outcome was recovery at 3-months post discharge. ROC-curve analyses were used to determine cut-off values and area under the curve (AUC), and logistic regression analyses to calculate odds ratios (ORs). Results The analytic sample included 174 participants with a mean (standard deviation) age of 79.2 (6.7) years of whom 84/174 (48%) were frail. At 3-months, 109/174 participants (63%) had recovered of whom 48 were frail. In all participants, determined cut-off values were 1369 steps/day (OR: 2.7, 95% confidence interval [CI]: 1.3–5.9, AUC 0.7) and 76 min/day of light intensity PA (OR: 3.9, 95% CI: 1.8–8.5, AUC 0.73). In frail participants, cut-off values were 1043 steps/day (OR: 5.0, 95% CI: 1.7–14.8, AUC 0.72) and 72 min/day of light intensity PA (OR: 7.2, 95% CI: 2.2–23.1, AUC 0,74). Determined cut-off values were not significantly associated with recovery in non-frail participants. Conclusions Post-discharge PA cut-offs indicate the odds of recovery in older adults, especially in frail individuals, however are not equipped for use as a diagnostic test in daily practice. This is a first step in providing a direction for setting rehabilitation goals in older adults after hospitalization.

Background To evaluate the effects of a shared decision making (SDM) intervention for older adults with multiple chronic conditions (MCCs). Methods A pragmatic trial evaluated the effects of the SDMMCC intervention, existing of SDM training for nine geriatricians in two hospitals and a preparatory tool for patients. A prospective pre-intervention post-intervention multi-center clinical study was conducted in which an usual care group of older patients with MCC and their informal caregivers was included before the implementation of the intervention and a new cohort of patients and informal caregivers after the implementation of the intervention. SDM was observed using the OPTIONMCC during video-recorded consultations. Patient- and caregivers reported outcomes regarding their role in SDM, involvement, perceived SDM and decisional conflict were measured. The differences between groups regarding the level of observed SDM (OPTIONMCC) were analyzed with a mixed model analysis. Dichotomous patient-reported outcomes were analyzed with a logistic mixed model. Results From two outpatient geriatric clinics 216 patients with MCCs participated. The mean age was 77.3 years, and 56.3% of patients were female. No significant difference was found in the overall level of SDM as measured with the OPTIONMCC or in patient-reported outcomes. However, at item level the items discussing ‘goals’, ‘options’, and ‘decision making’ significantly improved after the intervention. The items discussing ‘partnership’ and ‘evaluating the decision-making process’ showed a significant decrease. Fifty-two percent of the patients completed the preparatory tool, but the results were only discussed in 12% of the consultations. Conclusion This study provides scope for improvement of SDM in geriatrics. Engaging older adults with MCCs and informal caregivers in the decision making process should be an essential part of SDM training for geriatricians, beyond the SDM steps of explaining options, benefits and harms. More attention should be paid to the integration of preparatory work in the consultation.

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Background Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. Methods Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. Discussion In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. Trial registration This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022–000408-36.

Background Major depression is a highly prevalent disorder causing severe personal distress, and high societal costs. Patients with depression often have comorbid insomnia disorder (ID) leading to even worse personal distress and worse treatment outcomes. Recent results from a non-randomised pilot study with internet-delivered Cognitive Behavioural Therapy (CBTi) for Insomnia (I-Sleep) added to regular depression care were promising regarding feasibility and initial effects on insomnia complaints and depression. However, no randomised controlled trial (RCT) has been performed yet to access the (cost-) effectiveness of I-Sleep for depression. Therefore, this protocol article presents the design of an RCT aimed to assess the (cost-) effectiveness of I-Sleep in addition to usual care for depression compared to usual care alone in depressed patients with a comorbid Insomnia Disorder (ID) treated at outpatient clinics for mood disorders. Methods /design This is a multi-centre RCT with measurements at baseline and at 3, 6, 9, and 12 months of follow-up. Patients with depression and an ID are randomised to either I-Sleep treatment followed by regular depression care or to regular depression care alone. Our aim is to recruit one hundred and seventy-five patients from multiple outpatient clinics for mood disorders. The primary outcome is the change in depressive symptoms over 12 months of follow-up measured with the Patient Health Questionnaire (PHQ-9). Secondary outcomes are recovery from depression (PHQ-9), insomnia severity (Insomnia Severity Index, ISI), daily functioning (Work and Social Adjustment Scale, WSAS), general quality of life (EuroQol 5-level version, EQ-5D-5L), and societal costs (Adapted versions of the iMTA Productivity Cost Questionnaire, iPCQ and iMTA Medical Cost Questionnaire, iMCQ). Discussion We hypothesize that the addition of I-Sleep to usual care will result in a significant improvement in depression treatment outcomes and quality of life as well as a decrease in healthcare and societal costs compared to usual care alone. This study is the first pragmatic RCT evaluating the effectiveness and cost-effectiveness of adding CBTi to usual care for depression. Trial registration Netherlands Trial Register (NL8955). Registered on October 6th2020. https://trialsearch.who.int/Trial2.aspx?TrialID=NL8955

Background Smoking among people with severe mental illness (SMI) is highly prevalent and strongly associated with poor physical health. Currently, evidence-based smoking cessation interventions are scarce and need to be integrated into current mental health care treatment guidelines and clinical practice. Therefore, the present study aims to evaluate the implementation and effectiveness of a smoking cessation intervention in comparison with usual care in people with SMI treated by Flexible Assertive Community Treatment (FACT) teams in the Netherlands. Methods A pragmatic, cluster-randomised controlled trial with embedded process evaluation will be conducted. Randomisation will be performed at the level of FACT teams, which will be assigned to the KISMET intervention or a control group (care as usual). The intervention will include pharmacological treatment combined with behavioural counselling and peer support provided by trained mental health care professionals. The intervention was developed using a Delphi study, through which a consensus was reached on the core elements of the intervention. We aim to include a total of 318 people with SMI (aged 18–65 years) who smoke and desire to quit smoking. The primary outcome is smoking status, as verified by carbon monoxide measurements and self-report. The secondary outcomes are depression and anxiety, psychotic symptoms, physical fitness, cardiovascular risks, substance use, quality of life, and health-related self-efficacy at 12 months. Alongside the trial, a qualitative process evaluation will be conducted to evaluate the barriers to and facilitators of its implementation as well as the satisfaction and experiences of both patients and mental health care professionals. Discussion The results of the KISMET trial will contribute to the evidence gap of effective smoking cessation interventions for people treated by FACT teams. Moreover, insights will be obtained regarding the implementation process of the intervention in current mental health care. The outcomes should advance the understanding of the interdependence of physical and mental health and the gradual integration of both within the mental health care system. Trial registration Netherlands Trial Register, NTR9783. Registered on 18 October 2021.

Objectives To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training. Method Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates. Results huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003). Conclusion Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training.

Background Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5–7.8 mmol/L or 63–140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy. Methods In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18–45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c ( Discussion This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023. Trial registration ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971

Background Malnutrition (i.e., protein-energy malnutrition) in older adults has severe negative clinical consequences, emphasizing the need for effective treatments. Many, often small, randomized controlled trials (RCTs) testing the effectiveness of nutritional interventions for the treatment of malnutrition showed mixed results and a need for meta-analyses and data pooling has been expressed. However, evidence synthesis is hampered by the wide variety of outcomes and their method of assessment in previous RCTs. This paper describes the protocol for developing a Core Outcome Set (COS) for nutritional intervention studies in older adults with malnutrition and those at risk. Methods The project consists of five phases. The first phase consists of a scoping review to identify frequently used outcomes in published RCTs and select additional patient-reported outcomes. The second phase includes a modified Delphi Survey involving experienced researchers and health care professionals working in the field of malnutrition in older adults, followed by the third phase consisting of a consensus meeting to discuss and agree what critical outcomes need to be included in the COS. The fourth phase will determine how each COS outcome should be measured based on a systematic literature review and a second consensus meeting. This will be followed by a dissemination and implementation phase. Patient and Public Involvement (PPI) representatives will contribute to study design, oversight, consensus, and dissemination. Conclusions The result of this project is a COS that should be included in any RCT evaluating the effect of nutritional interventions in older adults with malnutrition and those at risk. This COS will facilitate comparison of RCT results, will increase efficient use of research resources and will reduce bias due to measurement of the outcome and publication bias. Ultimately, the COS will support clinical decision making by identifying the most effective approaches for treating and preventing malnutrition in older adults.

This paper investigated facilitators and barriers to implementing the European Football Fans in Training program (EuroFIT) in professional sports clubs in England, the Netherlands, Norway, and Portugal. We analyzed qualitative data collected at clubs that delivered EuroFIT, based on semi-structured interviews with coordinating staff (n = 15), coaches (n = 16), and focus group interviews with participants (n = 108), as well as data from clubs that considered delivering EuroFIT in the future, based on interviews with staff (n = 7) and stakeholders (n = 8). Facilitators for implementation related to the content and structure of the program, its evidence-base, and the context for delivery in the football stadia. Financial and human resources were both facilitators and barriers. Further barriers were mostly practical, relating to human resources and infrastructure. Major differences between countries related to experience and commitment to running community projects, and differences in infrastructure, financing, and human resources. Professional football clubs’ ability to support health promotion efforts depended on their ethos and the financial and human resources available to them. Overall, the EuroFIT program was well received by clubs, coaches, participants, and stakeholders, which was reflected by the many facilitators supporting sustained implementation. For sustainable implementation, it is crucial that clubs and their stakeholders engage fully with the EuroFIT program and understand that for an adequate program delivery their views (ethos) and ways of working influence the implementation and thereby the effectiveness of EuroFIT. An important prerequisite for future roll out of EuroFIT would be a strong EuroFIT delivery partner organization to ensure financial and human resources while overseeing and guiding the quality of delivery in clubs. Factors influencing the implementation of the EuroFIT lifestyle change program in professional football clubs in Europe: a qualitative study in four European countries

Background: Insomnia is the transdiagnostically shared most common complaint in disorders of anxiety, stress and emotion regulation. Current cognitive behavioral therapies (CBT) for these disorders do not address sleep, while good sleep is essential for regulating emotions and learning new cognitions and behaviours: the core fundaments of CBT. This transdiagnostic randomized control trial (RCT) evaluates whether guided internet-delivered cognitive behavioral therapy for insomnia (iCBT-I) (1) improves sleep, (2) affects the progression of emotional distress and (3) enhances the effectiveness of regular treatment of people with clinically relevant symptoms of emotional disorders across all mental health care (MHC) echelons. Methods: We aim for 576 completers with clinically relevant symptoms of insomnia as well as at least one of the dimensions of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), posttraumatic stress disorder (PTSD) or borderline personality disorder (BPD). Participants are either pre-clinical, unattended, or referred to general- or specialized MHC. Using covariate-adaptive randomization, participants will be assigned to a 5 to 8-week iCBT-I (i-Sleep) or a control condition (sleep diary only) and assessed at baseline, and after two and eight months. The primary outcome is insomnia severity. Secondary outcomes address sleep, severity of mental health symptoms, daytime functioning, mental health protective lifestyles, well-being, and process evaluation measures. Analyses use linear mixed-effect regression models. Discussion: This study can reveal for whom, and at which stage of disease progression, better nights could mean substantially better days. Trial registration: International Clinical Trial Registry Platform (NL9776). Registered on 2021-10-07.

Objective:Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate-for-gestational age. The aim of this study was to evaluate the associations between birth-weight centile and intellectual development in term/near-term infants across the entire birth-weight spectrum, in order to provide a basis for better understanding of the long-term implications of fetal growth restriction and reduced placental function.Methods:This was a population-based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003–2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016–2019. Regression analyses were conducted to assess the association of birth-weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501–550, and proportion of children who reached higher secondary school level.Results:Mean school performance score increased gradually with increasing birth-weight centile, from 533.6 in the 1st–5th birth-weight-centile group to 536.8 in the 81st–85th birth-weight-centile group. Likewise, the proportion of children at higher secondary school level increased with birth-weight centile, from 43% to 57%. Compared with the 81st–85th birth-weight-centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth-weight-centile groups below the 80th centile, after adjusting for confounding factors.Conclusions:Birth-weight centile is associated positively with school performance at 12 years of age across the entire birth-weight spectrum, well beyond the conventional and arbitrary cut-offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short- and long-term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Background: Ethnic minority groups experience a disproportionately high burden of infections, hospitalizations and mortality due to COVID-19, and therefore should be especially encouraged to receive SARS-CoV-2 vaccination. This study aimed to investigate the intent to vaccinate against SARS-CoV-2, along with its determinants, in six ethnic groups residing in Amsterdam, the Netherlands. Methods: We analyzed data of participants enrolled in the population-based multi-ethnic HELIUS cohort, aged 24 to 79 years, who were tested for SARS-CoV-2 antibodies and answered questions on vaccination intent from November 23, 2020 to March 31, 2021. During the study period, SARS-CoV-2 vaccination in the Netherlands became available to individuals working in healthcare or > 75 years old. Vaccination intent was measured by two statements on a 7-point Likert scale and categorized into low, medium, and high. Using ordinal logistic regression, we examined the association between ethnicity and lower vaccination intent. We also assessed determinants of lower vaccination intent per ethnic group. Results: A total of 2,068 participants were included (median age 56 years, interquartile range 46–63). High intent to vaccinate was most common in the Dutch ethnic origin group (369/466, 79.2%), followed by the Ghanaian (111/213, 52.1%), South-Asian Surinamese (186/391, 47.6%), Turkish (153/325, 47.1%), African Surinamese (156/362, 43.1%), and Moroccan ethnic groups (92/311, 29.6%). Lower intent to vaccinate was more common in all groups other than the Dutch group (P < 0.001). Being female, believing that COVID-19 is exaggerated in the media, and being < 45 years of age were common determinants of lower SARS-CoV-2 vaccination intent across most ethnic groups. Other identified determinants were specific to certain ethnic groups. Conclusions: Lower intent to vaccinate against SARS-CoV-2 in the largest ethnic minority groups of Amsterdam is a major public health concern. The ethnic-specific and general determinants of lower vaccination intent observed in this study could help shape vaccination interventions and campaigns.

The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage.

STUDY OBJECTIVES: We investigated the prevalence of self-reported insomnia symptoms in people with type 2 diabetes and assessed the association with metabolic outcomes and the mediating role of lifestyle factors. METHODS: In a prospective cohort of 1,272 participants with type 2 diabetes (63.4% male, age 68.7 ± 9 years) we measured insomnia symptoms using the Insomnia Severity Index and metabolic outcomes as hemoglobin A1c, glucose, lipids, and body mass index at baseline and at 1 year follow-up. Linear regression analyses assessed the association between insomnia symptoms and metabolic outcomes, corrected for demographic factors, comorbidities, and body mass index. Mediation analyses were conducted for lifestyle factors. RESULTS: The prevalence of mild and severe insomnia symptoms was 23.0% and 10.7%, respectively. When adjusted for demographic factors and comorbidities, cross-sectionally severe insomnia symptoms were associated with higher body mass index (β = 0.97 kg/m2; 95% confidence interval 0.04: 1.89) compared to no insomnia symptoms. Cross-sectionally, no associations were observed for the other metabolic outcomes. Additionally, no prospective associations were observed with any of the outcomes. Finally, physical activity mediated the association between severe insomnia symptoms and body mass index by 29.3%. CONCLUSIONS: About a third of people with type 2 diabetes experience self-reported insomnia symptoms, but insomnia symptoms were not associated with metabolic outcomes in people with type 2 diabetes. CITATION: Groeneveld L, den Braver NR, Beulens JWJ, et al. The prevalence of self-reported insomnia symptoms and association with metabolic outcomes in people with type 2 diabetes: the Hoorn Diabetes Care System cohort. J Clin Sleep Med. 2023;19(3):539-548.

Background: The WHO recommends soda taxes to reduce sugar consumption, but the effect across socioeconomic groups is unclear. Objectives: We assessed 16-y trends in daily soda consumption among adolescents in 4 European countries with a soda tax and 5 comparison countries, by family affluence. Methods: Five rounds of the international “Health Behaviour in School-Aged Children” school-based survey were used (school years 2001/2002 to 2017/2018, repeated cross-sectional design). Finland, France, Belgium, and Portugal introduced or updated a soda tax during this period. For comparison, we selected 5 neighboring countries without such a tax. Nationally representative samples of adolescents aged 13 and 15 y (n = 165,521; 51.2% girls) completed a standardized questionnaire, including a question on soda consumption frequency. Using the family affluence scale (FAS), we categorized adolescents into lower-, middle- or higher-affluent groups. Changes in daily soda consumption were assessed in each country independently. Results: Before taxation, daily soda consumption was more likely among lower-affluent adolescents in France and Belgium (P < 0.001, socioeconomic inequalities) and was similar across FAS groups in Finland and Portugal (no inequalities). After the tax, daily soda consumption was reduced across all FAS groups in Finland, Belgium, and Portugal (P interactions ≥ 0.33). In France, a posttax decrease was observed only among lower-affluent adolescents (OR lower, 0.76; 95% CI: 0.60, 0.96; reduced inequalities). During the same periods, socioeconomic patterns remained stable in 3 comparison countries (P interactions ≥ 0.38), and larger reductions in daily soda consumption were observed among middle- or higher-affluent adolescents compared with lower-affluent adolescents in the remaining 2 comparison countries (P interactions ≤ 0.08, increased inequalities). Conclusions: Socioeconomic patterns did not change after the tax implementation in 3 out of 4 countries, and socioeconomic inequalities were reduced in France. Taxing sodas might be an effective measure to attenuate, or at least not exacerbate, socioeconomic inequalities in adolescent daily soda consumption. Am J Clin Nutr 20XX;xx:xx–xx.

Background: The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. Research design and methods: Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case–control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. Results: Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25–0.63 events per 100 person-years for intracranial bleeding, 0.49–1.72 for gastrointestinal bleeding, and 0.27–0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30–0.80, 0.30–1.42, and 0.24–0.42, respectively. In the nested case–control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. Conclusions: Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Background Telephone triage is fully integrated in Dutch out-of-hours primary care (OOH-PC). Patients presenting with chest pain are initially assessed according to a standardized protocol (“Netherlands Triage Standard” [NTS]). Nevertheless, little is known about its (diagnostic) performance, nor on the impact of subsequent clinical judgements made by triage assistants and general practitioners (GPs). Objective To evaluate the performance of the current NTS chest pain protocol. Methods Observational, retrospective cohort study of adult patients with chest pain who contacted a regional OOH-PC facility in the Netherlands, in 2017. The clinical outcome measure involved the occurrence of a “major event,” which is a composite of all-cause mortality and urgent cardiovascular and noncardiovascular conditions, occurring ≤6 weeks of initial contact. We assessed the performance using diagnostic and discriminatory properties. Results In total, 1,803 patients were included, median age was 54.0 and 57.5% were female. Major events occurred in 16.2% of patients with complete follow-up, including 99 (6.7%) cases of acute coronary syndrome and 22 (1.5%) fatal events. NTS urgency assessment showed moderate discriminatory abilities for predicting major events (c-statistic 0.66). Overall, NTS performance showed a sensitivity and specificity of 83.0% and 42.4% with a 17.0% underestimated major event rate. Triage assistants’ revisions hardly improved urgency allocation. Further consideration of the clinical course following OOH-PC contact did generate a more pronounced improvement with a sensitivity of 89.4% and specificity of 61.9%. Conclusion Performance of telephone triage of chest pain appears moderate at best, with acceptable safety yet limited efficiency, even after including further work-up by GPs.

Purpose Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC–MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07–5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Background: Conflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease. Aims: To identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations. Methods: A systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models. Results: Of the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33–2.12; I2 = 69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08–1.50; I2 = 38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26–3.39; I2 = 78%); stroke (HR 1.59, 95% CI 1.29–1.96; I2 = 45%); sudden cardiac death (HR 1.60, 95% CI 1.14–2.25; I2 = 68%); and atrial fibrillation (HR 1.55, 95% CI 1.31–1.83; I2 = 0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population. Conclusion: QTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population.

Background Numerous prediction models estimating the risk of complications after esophagectomy exist but are rarely used in practice. The aim of this study was to compare the clinical judgment of surgeons using these prediction models. Methods Patients with resectable esophageal cancer who underwent an esophagectomy were included in this prospective study. Prediction models for postoperative complications after esophagectomy were selected by a systematic literature search. Clinical judgment was given by three surgeons, indicating their estimated risk for postoperative complications in percentage categories. The best performing prediction model was compared with the judgment of the surgeons, using the net reclassification improvement (NRI), category-free NRI (cfNRI), and integrated discrimination improvement (IDI) indexes. Results Overall, 159 patients were included between March 2019 and July 2021, of whom 88 patients (55%) developed a complication. The best performing prediction model showed an area under the receiver operating characteristic curve (AUC) of 0.56. The three surgeons had an AUC of 0.53, 0.55, and 0.59, respectively, and all surgeons showed negative percentages of cfNRIevents and IDIevents, and positive percentages of cfNRInonevents and IDIevents. This indicates that in the group of patients with postoperative complications, the prediction model performed better, whereas in the group of patients without postoperative complications, the surgeons performed better. NRIoverall was 18% for one surgeon, while the remainder of the NRIoverall, cfNRIoverall and IDIoverall scores showed small differences between surgeons and the prediction models. Conclusion Prediction models tend to overestimate the risk of any complication, whereas surgeons tend to underestimate this risk. Overall, surgeons’ estimations differ between surgeons and vary between similar to slightly better than the prediction models.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Methods: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Results: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. Conclusions: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Keywords: Mendelian randomization; celiac disease; gastrointestinal disease; genetic correlation; inflammatory bowel disease; migraine.

Background: Problematic sleep in infants can have a high impact on families. We examined parental discontent with infant sleep in the first six months of life and parent-perceived problematic sleep during the second year of life. Methods: We used Sarphati Cohort data of 1471 children. During periodic youth health care visits in the first six months of life, professionals registered parental discontent with infant sleep. In the second year of life, parents filled out the Brief Infant Sleep Questionnaire (BISQ), from which we defined parent-perceived problematic sleep and BISQ-defined problematic sleep. We examined the association of parental discontent with infant sleep during the first six months with both BISQ-derived outcomes up to age two, using multivariable logistic regression analysis. Results: 26% of parents were discontented with infant sleep during the first six months of life. During the second year of life, 27% of the parents perceived their child’s sleep as problematic, and 9% of the infants had BISQ-defined problematic sleep. Early parental discontent with infant sleep was associated with parent-perceived problematic sleep [adjusted OR 2.50 (95% CI 1.91–3.28)], and BISQ-defined problematic sleep [adjusted OR 1.88 (1.11–3.17)]. Conclusions: Early registered parental discontent with infant sleep was a predictor of parent-perceived problematic sleep in early toddlerhood. Registering parental discontent during infancy might enable professionals to identify a group of infants at risk for later problematic sleep. We recommend screening and parental support for sleep difficulties in an early stage.

BACKGROUND Since the birth of the first baby using IVF technology in 1978, over 10 million children have been conceived via ART. Although most aspects of ARTs were developed in animal models, the introduction of these technologies into clinical practice was performed without comprehensive assessment of their long-term safety. The monitoring of these technologies over time has revealed differences in the physiology of babies produced using ARTs, yet due to the pathology of those presenting for treatment, it is challenging to separate the cause of infertility from the effect of treatments offered. The use of systematic review and meta-analysis to investigate the impacts of the predominant ART interventions used clinically in human populations on animals produced in healthy fertile populations offers an alternative approach to understanding the long-term safety of reproductive technologies. OBJECTIVE AND RATIONALE This systematic review and meta-analysis aimed to examine the evidence available from animal studies on physiological outcomes in the offspring conceived after IVF, IVM or ICSI, compared to in vivo fertilization, and to provide an overview on the landscape of research in this area. SEARCH METHODS PubMed, Embase and Commonwealth Agricultural Bureaux (CAB) Abstracts were searched for relevant studies published until 27 August 2021. Search terms relating to assisted reproductive technology, postnatal outcomes and mammalian animal models were used. Studies that compared postnatal outcomes between in vitro-conceived (IVF, ICSI or IVM) and in vivo-conceived mammalian animal models were included. In vivo conception included mating, artificial insemination, or either of these followed by embryo transfer to a recipient animal with or without in vitro culture. Outcomes included birth weight, gestation length, cardiovascular, metabolic and behavioural characteristics and lifespan. OUTCOMES A total of 61 studies in five different species (bovine, equine, murine, ovine and non-human primate) met the inclusion criteria. The bovine model was the most frequently used in IVM studies (32/40), while the murine model was mostly used in IVF (17/20) and ICSI (6/8) investigations. Despite considerable heterogeneity, these studies suggest that the use of IVF or maturation results in offspring with higher birthweights and a longer length of gestation, with most of this evidence coming from studies in cattle. These techniques may also impair glucose and lipid metabolism in male mice. The findings on cardiovascular outcomes and behaviour outcomes were inconsistent across studies. WIDER IMPLICATIONS Conception via in vitro or in vivo means appears to have an influence on measurable outcomes of offspring physiology, manifesting differently across the species studied. Importantly, it can be noted that these measurable differences are noticeable in healthy, fertile animal populations. Thus, common ART interventions may have long-term consequences for those conceived through these techniques, regardless of the pathology underpinning diagnosed infertility. However, due to heterogeneous methods, results and measured outcomes, highlighted in this review, it is difficult to draw firm conclusions. Optimizing animal and human studies that investigate the safety of new reproductive technologies will provide insight into safeguarding the introduction of novel interventions into the clinical setting. Cautiously prescribing the use of ARTs clinically may also be considered to reduce the chance of promoting adverse outcomes in children conceived before long-term safety is confidently documented.

After multiple waves of the COVID-19 pandemic, it has become clear that the impact of SARS-CoV-2 will carry on for years to come. Acutely infected patients show a broad range of disease severity, depending on virus variant, vaccination status, age and the presence of underlying medical and physical conditions, including obesity. Additionally, a large number of patients who have been infected with the virus present with post-COVID syndrome. In September 2020, the International Society for the Advancement of Respiratory Psychophysiology organized a virtual interest meeting on ‘Respiratory research in the age of COVID-19’, which aimed to discuss how research in respiratory psychophysiology could contribute to a better understanding of psychophysiological interactions in COVID-19. In the resulting current paper, we propose an interdisciplinary research agenda discussing selected research questions on acute and long-term neurobiological, physiological and psychological outcomes and mechanisms related to respiration and the airways in COVID-19, as well as research questions on comorbidity and potential treatment options, such as physical rehabilitation.

Background: Hypertensive disorders of pregnancy are associated with cardiovascular disease later in life. Given that hypertensive disorders of pregnancy often occur at a relatively young age, there might be an opportunity to use preventive measures to reduce the risk of early cardiovascular disease and mortality. The aim of this study was to assess the risk of cardiovascular mortality in women after a hypertensive disorder of pregnancy. Methods: In this population-based cohort study, the Netherlands Perinatal Registry (PRN) and the national death registry at the Dutch Central Bureau for Statistics were linked. We analysed women in the Netherlands with a first birth during 1995–2015 to determine the association between cardiovascular mortality and hypertensive disorders of pregnancy (based on recorded diastolic blood pressure or proteinuria, or both). We analysed the association between the highest diastolic blood pressure measured in pregnancy and cardiovascular mortality and constructed survival curves to assess cardiovascular mortality after hypertensive disorders of pregnancy, specifically pre-eclampsia and gestational hypertension. To differentiate between the severity of hypertensive disorders of pregnancy, cardiovascular mortality was assessed in women with a combination of hypertensive disorders of pregnancy with preterm birth (gestational age