Real-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review... Show moreReal-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making. A scoping review was conducted using literature databases (PubMed, Embase, Emcare, Web of Science, and Cochrane Library) and websites of regulatory agencies, health technology assessment agencies, research institutes, and professional organizations involved with RWE. Articles were included if: (1) they discussed factors or contexts that impact whether RWE could be necessary or desirable in regulatory decision making; (2) focused on pharmacological or biological interventions in humans; and (3) considered decision making in Europe or North America, or without a focus on a specific region. We included 118 articles in the scoping review. Two major themes and six subthemes were identified. The first theme concerns questions addressable with RWE, with subthemes epidemiology and benefit-risk assessment. The second theme concerns contextual factors, with subthemes feasibility, ethical considerations, limitations of available evidence, and disease and treatment-specific aspects. Collectively, these themes encompassed 43 factors influencing the need for RWE in regulatory decisions. Although single factors may not make RWE fully necessary, their cumulative influence could make RWE essential and pivotal in regulatory decision making. This overview contributes to ongoing discussions emphasizing the nuanced interplay of factors influencing the necessity or desirability of RWE to inform regulatory decision making. Show less
Nemeth, B.; Smeets, M.; Pedersen, A.B.; Kristiansen, E.B.; Nelissen, R.; Whyte, M.; ... ; Arya, R. 2024
Background: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. Objectives: To... Show moreBackground: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. Objectives: To develop and validate a prediction model for 90-day VTE risk. Methods: A multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development. Results: In the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study. Conclusion: This clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual’s risk for VTE following THA/TKA. Show less
Tweel, M.M. van den; Munckhof, E.H.A. van den; Zanden, M. van der; Molijn, A.C.; Lith, J.M.M. van; Cessie, S. le; Boers, K.E. 2023
PurposeThis study investigates the role of bacterial vaginosis (BV) on pregnancy rates during various fertility treatments. BV is known to influence several obstetric outcomes, such as preterm... Show morePurposeThis study investigates the role of bacterial vaginosis (BV) on pregnancy rates during various fertility treatments. BV is known to influence several obstetric outcomes, such as preterm delivery and endometritis. Only few studies investigated the effect of BV in subfertile women, and studies found a negative effect on fecundity especially in the in vitro fertilisation population.MethodsObservational prospective study, 76 couples attending a fertility clinic in the Netherlands between July 2019 and June 2022, undergoing a total of 133 attempts of intra uterine insemination, in vitro fertilization or intra cytoplasmatic sperm injection. Vaginal samples taken at oocyte retrieval or insemination were analysed on qPCR BV and 16S rRNA gene microbiota analysis of V1-V2 region. Logistic regression with a Generalized Estimated Equations analysis was used to account for multiple observations per couples.ResultsA total of 26% of the 133 samples tested positive for BV. No significant differences were observed in ongoing pregnancy or live birth rates based on BV status (OR 0.50 (0.16-1.59), aOR 0.32 (0.09-1.23)) or microbiome community state type. There was a tendency of more miscarriages based on positive BV status (OR 4.22 (1.10-16.21), aOR 4.28 (0.65-28.11)) or community state type group III and IV. On baseline qPCR positive participants had significantly higher body mass index and smoked more often. Odds ratios were adjusted for smoking status, body mass index, and socioeconomic status.ConclusionBacterial vaginosis does not significantly impact ongoing pregnancy rates but could affect miscarriage rates. Show less
Heckert, S.L.; Maassen, J.M.; Cessie, S. le; Goekoop-Ruiterman, Y.P.M.; Güler-Yüksel, M.; Lems, W.; ... ; Allaart, C.F. 2023
Objectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt ... Show moreObjectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt (BehandelStrategieen) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)<= 2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed.Results Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy.Conclusions After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor. Show less
Camilleri, E.; Smit, D.L.; Rein, N. van; Cessie, S. le; Hon, O. de; Heijer, M. den; ... ; Ronde, W. de 2023
Background: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with... Show moreBackground: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. Methods: The HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. Results: Participants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM*min (95% CI: -205 to -124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. Conclusion: During AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state. Show less
Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation... Show moreRationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy.Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (Pa-O2, 55-80mmHg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (Pa-O2, 110-150mmHg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included.Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved Pa-O2 was 75mmHg (interquartile range, 70-84) and 115mmHg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively.Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Show less
Van't Oever, R.M.; Zwiers, C.; Haas, M. de; Cessie, S. le; Lopriore, E.; Oepkes, D.; Verweij, E.J.T. 2023
ObjectivePregnant women who received at least one intrauterine transfusion (IUT) for haemolytic disease of the fetus and newborn (HDFN) in the preceding pregnancy are presumed to have a high... Show moreObjectivePregnant women who received at least one intrauterine transfusion (IUT) for haemolytic disease of the fetus and newborn (HDFN) in the preceding pregnancy are presumed to have a high likelihood of requiring IUTs again, often starting at an earlier gestational age. Our aim was to quantify these risks in a large national cohort.DesignRetrospective cohort study of a nationwide Dutch database.SettingThe Netherlands.PopulationAll women treated in The Netherlands with IUTs for Rhesus D (RhD)- or Kell-mediated HDFN between 1999 and 2017 and their follow-up pregnancies were included. Pregnancies with an antigen-negative fetus were excluded.MethodsElectronic patient files were searched for the number and gestational age of each IUT, and analysed using descriptive statistics and linear regression.Main outcome measuresPercentage of women requiring one or more IUTs again in the subsequent pregnancy, and gestational age at first IUT in both pregnancies.ResultsOf the 321 women in our study population, 21% (69) had a subsequent ongoing pregnancy at risk. IUTs were administered in 86% (59/69) of cases. In subsequent pregnancies, the median gestational age at first IUT was 3 weeks earlier (interquartile range -6.8 to 0.4) than in the preceding pregnancy.ConclusionsOur study shows that pregnant women with a history of IUTs in the previous pregnancy are highly likely to require IUTs again, and on average 3 weeks earlier. Clinicians need to be aware of these risks and ensure timely referral, and close surveillance from early pregnancy onwards. Additionally, for women with a history of IUT and their caregivers, this information is essential to enable adequate preconception counselling. Show less
Martens, L.G.; Hamersveld, D. van; Cessie, S. le; Dijk, K.W. van; Heemst, D. van; Noordam, R. 2023
Objectives: Low socioeconomic status (SES) is associated with cardiovascular risk factors and increased coronary artery disease (CAD) risk. We tested whether SES is an effect modifier of the... Show moreObjectives: Low socioeconomic status (SES) is associated with cardiovascular risk factors and increased coronary artery disease (CAD) risk. We tested whether SES is an effect modifier of the association between classical cardiovascular risk factors and CAD using SES-stratified Mendelian Randomization in European-ancestry participants from UK Biobank.Study Design and Setting: We calculated weighted genetic risk scores (GRS) for the risk factors body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, and triglycerides. Participants were stratified by Townsend deprivation index score. Lo-gistic regression models were used to investigate associations between GRSs and CAD occurrence. Additionally, stratification based on GRS-adjusted Townsend deprivation index residuals was conducted to correct for possible collider-stratification bias.Results: In a total sample size of N 5 446,485, with 52,946 cases, the risk for CAD per standard deviation increase in genetically influenced BMI was highest in the group with the lowest 25% SES (odds ratio: 1.126, 95% confidence interval: 1.106-1.145; odds ratio: 1.081, 95% confidence interval: 1.059-1.103 in high SES), remaining similar after controlling for possible collider-stratification bias. The effects of genetically influenced systolic blood pressure, low-density lipoprotein cholesterol, and triglyceride on CAD were similar between SES groups.Conclusion: CAD risk attributable to increased BMI is not homogenous and could be modified by SES. This emphasizes the need of tailor-made approaches for BMI-associated CAD risk reduction. & COPY; 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Rationale & Objective: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between... Show moreRationale & Objective: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5.Study Design: Prospective observational cohort study.Setting & Participants: We followed 1,714 patients (>= 65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m(2) measurement. Exposure: Serum potassium was measured every 3 to 6 months and categorized as <= 3.5, >3.5-<= 4.0, >4.0-<= 4.5, >4.5-<= 5.0 (reference), >5.0-<= 5.5, >5.5-<= 6.0, and >6.0 mmol/L.Outcome: The combined outcome death before KRT or start of KRT.Analytical Approach: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA).Results: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76 +/- 7 (SD) years, mean eGFR was 17 +/- 5 (SD) mL/min/1.73 m(2), and mean SGA was 6.0 +/- 1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9 mmol/L.Limitations: Shorter intervals between potassium measurements would have allowed for more precise estimations.Conclusions: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4- 5, with a nadir risk at a potassium level of 4.9 mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5. Show less
Background We explored the potential of emerging and conventional urinary kidney injury biomarkers in recipients of living donor (LD) or donation after circulatory death (DCD) kidney... Show moreBackground We explored the potential of emerging and conventional urinary kidney injury biomarkers in recipients of living donor (LD) or donation after circulatory death (DCD) kidney transplantation, patients with chronic kidney disease (CKD), and individuals from the general population. Methods Urine samples from kidney allograft recipients with mild (LD; n = 199) or severe (DCD; n = 71) ischemia-reperfusion injury (IRI) were analyzed for neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), chemokine C-X-C motif (CXCL9), solute carrier family 22 member 2 (SLC22A2), nephrin, and uromodulin (UMOD) by quantitative multiplex LC-MS/MS analysis. The fold-change in biomarker levels was determined in mild and severe IRI and in patients with CKD stage 1-2 (n = 127) or stage & GE;3 (n = 132) in comparison to the general population (n = 1438). Relationships between the biomarkers and total protein, & beta;2-microglobulin (B2M), creatinine, and osmolality were assessed. Results NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, and UMOD were quantifiable, whereas nephrin and SLC22A2 were below the limit of detection. Kidney injury biomarkers were increased up to 6.2-fold in allograft recipients with mild IRI and 8.3-fold in recipients with severe IRI, compared to the reference population, with the strongest response observed for NGAL and B2M. In CKD stage 1-2, B2M, NGAL, IGFBP7, TIMP2, KIM-1, UMOD, and CXCL9 were not altered, but in individuals with CKD stage & GE;3, B2M, NGAL, and KIM-1 were increased up to 1.3-fold. IGFBP7, TIMP2, NGAL, and CXCL9 were strongly correlated (all r & GE; 0.8); correlations with B2M and TP were smaller (all r & LE; 0.6). Conclusions IRI, but not stable CKD, was associated with increased urinary levels of kidney injury biomarkers determined by LC-MS/MS. Absolute and multiplexed protein quantitation by LC-MS/MS is an effective strategy for biomarker panel evaluation for translation toward the clinical laboratory. Show less
Verhagen, I.E.; Lentsch, S.D.; Arend, B.W.H. van der; Cessie, S. le; MaassenVanDenBrink, A.; Terwindt, G.M. 2023
Background and purpose Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies effectively reduce overall migraine attack frequency, but whether there are differences in effect between... Show moreBackground and purpose Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies effectively reduce overall migraine attack frequency, but whether there are differences in effect between perimenstrual and nonperimenstrual migraine days has not been investigated.Methods We performed a single-arm study among women with migraine. Participants were followed with electronic E-diaries during one (pretreatment) baseline month and 6 months of treatment with either erenumab or fremanezumab. Differences in treatment effect on perimenstrual and nonperimenstrual migraine days were assessed using a mixed effects logistic regression model, with migraine day as dependent variable; treatment, menstrual window, and an interaction term (treatment x menstrual window) as fixed effects; and patient as a random effect.Results There was no interaction between the menstrual window and treatment effect, indicating that the reduction in migraine days under treatment was similar during the menstrual window and the remainder of the menstrual cycle (odds ratio for treatment = 0.44, 95% confidence interval = 0.38-0.51).Conclusions Our findings support prophylactic use of anti-CGRP (receptor) antibodies for women with menstrual migraine, as this leads to consistent reductions in number of migraine days during the entire menstrual cycle. Show less
In clinical settings, the absolute risk reduction due to treatment that can be expected in a particular patient is of key interest. However, logistic regression, the default regression model for... Show moreIn clinical settings, the absolute risk reduction due to treatment that can be expected in a particular patient is of key interest. However, logistic regression, the default regression model for trials with a binary outcome, produces estimates of the effect of treatment measured as a difference in log odds. We explored options to estimate treatment effects directly as a difference in risk, specifically in the network meta-analysis setting. We propose a novel Bayesian (meta-)regression model for binary outcomes on the additive risk scale. The model allows treatment effects, covariate effects, interactions and variance parameters to be estimated directly on the linear scale of clinical interest. We compared effect estimates from this model to (1) a previously proposed additive risk model by Warn, Thompson and Spiegelhalter ( "WTS model ") and (2) backtransforming the predictions from a logistic model to the natural scale after regression. The models were compared in a network meta-analysis of 20 hepatitis C trials, as well as in the analysis of simulated single trial settings. The resulting estimates diverged, in particular for small sample sizes or true risks close to 0% or 100%. Researchers should be aware that modelling untransformed risk can yield very different results from default logistic models. The treatment effect in participants with such extreme predicted risks weighed more heavily on the overall treatment effect estimate from our proposed model compared to the WTS model. In our network meta-analysis, this sensitivity of our proposed model was needed to detect all information in the data. Show less
Verhagen, I.E.; Arend, B.W.H. van der; Casteren, D.S. van; Cessie, S. le; MaassenVanDenBrink, A.; Terwindt, G.M. 2023
Objective: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men.Background: Women report... Show moreObjective: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men.Background: Women report longer migraine attacks and more accompanying symptoms than men in cross-sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general.Methods: This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was "attack" duration. Differences between perimenstrual (Days -2 to +3 of the menstrual cycle) and non-perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache.Results: A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1-Q3]) attack duration in men was 32.1 [17.7-53.6] h, compared to 36.7 [21.9-62.4] h for non-perimenstrual migraine attacks and 44.4 [17.9-79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47-1.79; p < 0.001) and non-perimenstrual 1.15 (95% CI 1.05-1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non-perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93-2.95; p < 0.001), but not for non-perimenstrual (OR 1.18, 95% CI 0.97-1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura.Conclusion: Compared to attacks in men, both perimenstrual and non-perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex-specific approach to migraine treatment and research is needed. Show less
Ill-defined research questions could be particularly problematic in an epidemiological setting where measurements fluctuate over time due to intercurrent events, such as medication use. When a... Show moreIll-defined research questions could be particularly problematic in an epidemiological setting where measurements fluctuate over time due to intercurrent events, such as medication use. When a research question fails to specify how medication use should be handled methodologically, arbitrary decisions may be made during the analysis phase, which likely leads to a mismatch between the intended question and the performed analysis. The mismatch can result in vastly different or meaningless interpretations of estimated effects. Thus, a research question such as "what is the effect of X on Y? " requires further elaboration, and it should consider whether and how medication use has affected the measurements of interest. In our study, we will discuss how well-defined questions can be formulated when medication use is involved in observational studies. We will distinguish between a situation where an exposure is affected by medication use and where the outcome of interest is affected by medication use. For each setting, we will give examples of different research questions that could be asked depending on how medication use is considered in the estimand and discuss methodological considerations under each question. Show less
Christen, T.; Mutsert, R. de; Lamb, H.J.; Dijk, K.W. van; Cessie, S. le; Rosendaal, F.R.; ... ; Trompet, S. 2021
High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk,... Show moreHigh adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NTproBNP as the main marker of heart failure on adiponectin using Mendelian randomisation. Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial). The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m2. Per five mu g/ mL higher adiponectin, the E/A ratio was -0.05 (95 % CI: -0.10, -0.01) lower, left ventricle ejection fraction was -0.5 % (95 % CI: -1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: -0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher. With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies. Show less
Fosse, N.A. du; Lashley, E.E.L.O.; Treurniet, T.T.; Lith, J.M.M. van; Cessie, S. le; Boosman, H.; Hoorn, M.L.P. van der 2021
Background International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for... Show moreBackground International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for supportive care have been identified and women's preferences have been quantified. Although it is known that RPL impacts the mental health of both partners, male preferences for supportive care have hardly been explored. Methods A cross-sectional study was conducted in couples who visited a specialized RPL clinic in the Netherlands between November 2018 and December 2019. Both members of the couples received a questionnaire that quantified their preferences for supportive care in a next pregnancy and they were asked to complete this independently from each other. Preferences for each supportive care option were analysed on a group level (by gender) and on a couple level, by comparing preferences of both partners. Results Ninety-two questionnaires (completed by 46 couples) were analysed. The overall need for supportive care indicated on a scale from 1 to 10 was 6.8 for men and 7.9 for women (P = 0.002). Both genders preferred to regularly see the same doctor with knowledge of their obstetric history, to make a plan for the first trimester and to have frequent ultrasound examinations. A lower proportion of men preferred a doctor that shows understanding (80% of men vs. 100% of women, P = 0.004) and a doctor that informs on wellbeing (72% vs. 100%, P = <= 0.000). Fewer men preferred support from friends (48% vs. 74%, P = 0.017). Thirty-seven percent of men requested more involvement of the male partner at the outpatient clinic, compared to 70% of women (P = 0.007). In 28% of couples, partners had opposing preferences regarding peer support. Conclusions While both women and men affected by RPL are in need of supportive care, their preferences may differ. Current supportive care services may not entirely address the needs of men. Health care professionals should focus on both partners and development of novel supportive care programs with specific attention for men should be considered. Show less
Verkouter, I.; Noordam, R.; Loh, N.Y.; Dijk, K.W. van; Zock, P.L.; Mook-Kanamori, D.O.; ... ; Mutsert, R. de 2021
Context: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy.Objective: We aimed to study the specific metabolomic profile of adult weight... Show moreContext: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy.Objective: We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume.Methods: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n=6347, discovery) and Oxford Biobank (n=6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n=114) to estimate adipocyte volume.Results: Mean (SD) weight gain was 4.5 (3.7) kg/m(2) in the NEO study and 3.6 (3.7) kg/m(2) in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 mu m(3) (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain.Conclusion: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease. Show less
Eijmael, M.; Janssens, N.; Cessie, S. le; Dooren, Y. van; Koster, T.; Karim, F. 2021
Purpose Eosinopenia has been described in COVID-19. With this study, we aim to study the peripheral blood eosinophil counts in COVID-19 patients and to investigate whether there is an association... Show morePurpose Eosinopenia has been described in COVID-19. With this study, we aim to study the peripheral blood eosinophil counts in COVID-19 patients and to investigate whether there is an association between the peripheral blood eosinophil counts and disease severity of COVID-19. Methods We revised the electronical medical records of confirmed COVID-19 patients with polymerase chain reaction (PCR) assays in the Groene Hart Ziekenhuis, Gouda, The Netherlands. We divided patients in mild, moderate and severe groups based on clinical severity of COVID-19. Clinical severity was based on the therapy needed and the outcome of patients. We compared clinical characteristics, laboratory results and outcome between the three groups. Results Of the 230 patients included in this study, the mild, moderate and severe groups consisted of 16.5%, 45.7% and 37.8% of the included patients, respectively. The mean age was 68 years (IQR 57-78). 63% of patients were male. A significant decrease in the peripheral eosinophil counts was found corresponding to the increase of COVID-19 severity. In the mild, moderate and severe groups, the percentage of patients with eosinopenia was 73.7%, 86.7% and 94.3%, respectively (p value 0.002). Conclusion Eosinopenia is significantly more frequent present in patients with a severe COVID-19. Show less
OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase,... Show moreOBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library. STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines. Show less
Background: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal... Show moreBackground: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size.Methods: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naive patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months.Discussion: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. Show less
