Let’s talk and let’s snooze!:Patient-reported outcomes and sleep in type 2 diabetes

In Part I of this thesis, we provided an overview of PROMs for T2D. In chapter 2, we provided an overview of available PROMs to measure HRQoL in people with T2D. Over 160 PROMs for T2D were identified, with a large number of PROMs not measuring HRQoL at all, illustrating the poor quality and lack of consensus on which PROMs to use in research and care for people with T2D. In addition, in chapter 3, we tested if Computerized Adaptive Tests (CATs) are a solution for implementation of PROMs in T2D care. In 314 people with T2D, we assessed the psychometric properties of seven PROMIS CATs (assessing 1) Physical Function, 2) Pain Interference, 3) Fatigue, 4) Sleep Disturbance, 5) Anxiety, 6) Depression, and 7) Ability to Participate in Social Roles and Activities) that are relevant to people with T2D. Additionally, we assessed their acceptability in health care providers and people with T2D through focus groups and interviews. We showed that these CATs showed sufficient validity and reliability, though caution was advised regarding their responsiveness as our participants showed little change over our study period of six months. During the focus groups and interviews both health care providers and people with T2D suggested that CATs could serve as a conversation starter in routine care, but CATs should never replace personal consultations with a doctor. The second part of the thesis focused on sleep, which is also intricately linked to T2D. Previous research indicates associations between inadequate sleep duration, poor sleep quality, irregular sleep patterns and sleep disorders resulting in an increased risk of T2D and worse T2D progression. Research gaps exist in understanding specific aspects of sleep's contribution to T2D risk and progression, necessitating further exploration and intervention studies. In chapter 4, we therefore investigated the prevalence of self-reported insomnia symptoms and their association with metabolic outcomes, additionally exploring the possible mediating role of lifestyle factors in a prospective cohort of 1272 people with T2D. Approximately a third of the cohort indicated to experience symptoms of insomnia. Furthermore, cross-sectionally, insomnia symptoms were associated with poorer metabolic outcomes, but no prospective associations were observed. Finally, lifestyle factors only partly mediated the association between insomnia symptoms and metabolic outcomes. As the prevalence of insomnia symptoms is high in people with T2D and it is associated with metabolic outcomes, treatment of insomnia symptoms could contribute to the treatment of T2D. In chapter 5, we therefore described our randomized controlled trial on the effect of Cognitive Behavioral Therapy for Insomnia (CBT-I) on glycemic and metabolic outcomes in people with T2D, compared to care as usual. This study in 57 participants showed no statistically significant differences in glycemic and metabolic outcomes or Quality of Life (QoL), but did show a significantly larger decrease in insomnia symptoms and depressive symptoms after three and six months of cognitive behavioral therapy compared to control. Overall, this thesis emphasizes the need for Core Outcome Sets in PROMs for T2D, the value of PROMIS CATs in routine care, and the importance of addressing sleep disturbances in people with T2D in clinical practice. However, further research on relevant PROs and PROMs, especially future validation studies of diabetes-specific PROMs are needed, warranting a transdiagnostic integration of PROMs in diabetes research and clinical practice. Furthermore, sleep should become part of the standard evaluation protocol for people with T2D. In conclusion, the studies described in this thesis are an important addition to the literature and show that it is important to measure PROs or in other words - let’s talk! - as well as to sleep - let’s snooze! - in people with T2D

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Background & Aims: Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. Results: We identified three independent genetic variants (rs1800562 (C282Y) and rs1799945 (H63D) in HFE and rs855791 (V736A) in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p<5x10-8). The two HFE variants account for ~85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases

Using dynamic vegetation models to simulate plant range shifts

Peer reviewedPublisher PD

The effect of cognitive behavioral therapy for insomnia on sleep and glycemic outcomes in people with type 2 diabetes: A randomized controlled trial

Study objectives: Investigate whether aiding sleep by online cognitive behavioral therapy for insomnia (CBT-I) can improve glycemic and metabolic control, mood, quality of life (QoL) and insomnia symptoms in people with type 2 diabetes and assess the mediating role of lifestyle factors. Methods: Adults with type 2 diabetes and insomnia symptoms were randomly assigned to CBT-I or care as usual. At baseline, three and six months we assessed HbA1c as primary outcome and glycemic control, metabolic outcomes, sleep, mood and QoL as secondary outcomes. Mixed models were used to determine within-person and between-persons differences in outcomes and mediation analysis for lifestyle factors. Results: We randomized 29 participants to CBT-I and 28 to care as usual. Intention-to-treat analysis showed no significant differences in glycemic control, metabolic outcomes, anger, distress or QoL, but showed a significantly larger decrease in insomnia (−1.37(2.65: 0.09)) and depressive symptoms (−0.92(-1.77: 0.06)) and increase in BMI (0.29 kg/m2(0.00:0.57)) in the intervention compared to the control group. Only half of the intervention participants completed the CBT-I. Per protocol analysis showed a not statistically significant decrease in HbA1c (−2.10 mmol/l(-4.83:0.63)) and glucose (−0.39 mmol/l(-1.19:0.42)), metabolic outcomes and increase in QoL. Furthermore, the intervention group showed a significant decrease in insomnia (−2.22(-3.65: 0.78)) and depressive symptoms (−1.18(-2.17: 0.19)) compared to the control group. Lifestyle factors partially mediated the effect of the intervention. Conclusions: CBT-I might improve insomnia symptoms and mood, and perhaps improves glycemic control, albeit not significant, in people with type 2 diabetes and insomnia symptoms, compared to care as usual

The cross-sectional association between dietary total, animal, and plant-based protein intake and the prevalence and severity of depressive symptoms in Dutch adults with type 2 diabetes: The Hoorn Diabetes Care System cohort

Objective: This study aimed to investigate cross-sectional associations of total, animal, and plant-based protein intake and depressive symptoms in Dutch adults with type 2 diabetes (T2D). Methods: We included 1137 individuals with T2D (aged 68.6 ± 9.0) from the Hoorn Diabetes Care System cohort. Energy-adjusted protein intake was assessed using a validated Food Frequency Questionnaire. The nine-item Patient Health Questionnaire (PHQ-9) was used to assess the prevalence of depressive symptoms (PHQ-9 ≥ 10 and/or anti-depressant use) and the severity of depressive symptoms (continuous PHQ-9 score). Associations between total, animal, and plant-based protein (quartiles) with depressive symptoms were assessed using multiple logistic and linear regression. Results: Highest intake of total, animal, and plant-based protein was not associated with the prevalence of depressive symptoms, compared to lowest intake (e.g., total protein, ORQ4vsQ1:0.75, 95%CI 0.42;1.32). For the severity of depressive symptoms, highest total protein intake was significantly associated with lower PHQ-9 scores (ORQ4vsQ1:0.87, 95%CI 0.75;1.00), compared to lowest intake. Animal protein was not associated with the severity of depressive symptoms (β ∼ 1), while the association for plant-based protein was marginally non-significant (βQ4vsQ1:0.88, 95%CI 0.76;1.02). Conclusion: In individuals with T2D, higher total protein intake was associated with reduced severity of depressive symptoms, but not with the prevalence of depressive symptoms. Further prospective research with a larger sample size is needed to confirm these associations

The association between social jetlag and parameters of metabolic syndrome and type 2 diabetes: a systematic review and meta-analysis

This study aims to determine the association between social jetlag and parameters of metabolic syndrome and type 2 diabetes (T2D) in a systematic review and meta-analysis. A systematic literature search was conducted in PubMed/Embase/Scopus until May 2022. Included studies described an association between social jetlag and parameters of the metabolic syndrome and/or T2D, were available full text and written in English or Dutch. Data extraction and quality assessment were performed on pre-piloted forms independently by two reviewers. Results were meta-analysed using random-effects analysis. A total of 6,290 titles/abstracts were screened, 176 papers were read full-text, 68 studies were included. Three studies were rated as low quality, 27 were moderate, and 38 were high quality. High quality studies showed that having social jetlag compared to no social jetlag was significantly associated with higher body mass index in 20 studies (0.49 kg/m2, 95% confidence interval [CI] 0.21–0.77; I2 = 100%), higher waist circumference in seven studies (1.11 cm, 95% CI 0.42–1.80; I2 = 25%), higher systolic blood pressure in 10 studies (0.37 mmHg, 95% CI 0.00–0.74; I2 = 94%) and higher glycated haemoglobin in 12 studies (0.42%, 95% CI 0.12– 0.72; I2 = 100%). No statistically significant associations were found for obesity, abdominal obesity, high- and low-density lipoprotein levels, cholesterol, triglycerides, diastolic blood pressure, hypertension, fasting glucose, homeostatic model assessment for insulin resistance, metabolic syndrome or T2D. Sensitivity analyses did not reduce heterogeneity. Despite substantial heterogeneity, social jetlag is associated with certain parameters of the metabolic syndrome and T2D, but not with prevalent metabolic syndrome or T2D. These findings should be interpreted with caution as the level of evidence is low and mostly based on cross-sectional data. Longitudinal studies are needed to further assess the direction of causality

Sharing data for future research-engaging participants' views about data governance beyond the original project:a DIRECT Study

Purpose: Biomedical data governance strategies should ensure that data are collected, stored, and used ethically and lawfully. However, research participants' preferences for how data should be governed is least studied. The Diabetes Research on Patient Stratification (DIRECT) project collected substantial amounts of health and genetic information from patients at risk of, and with type II diabetes. We conducted a survey to understand participants' future data governance preferences. Results will inform the postproject data governance strategy.Methods: A survey was distributed in Denmark, Sweden, The Netherlands, and the United Kingdom.Results: In total 855 surveys were returned. Ninety-seven percent were supportive of sharing data postproject, and 90% were happy to share data with universities, and 56% with commercial companies. The top three priorities for data sharing were highly secure database, DIRECT researchers to monitor data used by other researchers, and researchers cannot identify participants. Respondents frequently suggested that a postproject Data Access Committee should involve a DIRECT researcher, diabetes clinician, patient representative, and a DIRECT participant.Conclusion: Preferences of how data should be governed, and what data could be shared and with whom varied between countries. Researchers are considered as key custodians of participant data. Engaging participants aids in designing governance to support their choices.</p

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570