[Causes of death: the uncertainty behind the numbers]. / Doodsoorzaken: de onzekerheid achter de cijfers.

When a person dies in the Netherlands it is legally required to report the cause of death. In most cases however, there is uncertainty when classifying causes of death. Additional postmortem diagnostics such as a CT scan or autopsy do not always provide absolute certainty. Data on causes of death can be used to determine what are, on a population level, relevant health problems. One must be cautious to fully rely on these data for making policy or financing healthcare and research. Firstly, incorrectly classifying the cause of death can give a distorted view of the underlying causes. Secondly, relevant health problems, such as obesity, might be overlooked in the statistics when they are not clearly a cause of death.

Directed acyclic graphs in clinical research.

Directed acyclic graphs (DAGs), or causal diagrams, are graphical representations of causal structures that can be used in medical research to understand and illustrate potential bias, including bias arising from confounding, selection, and misclassification. Further, they provide guidance for researchers about how to address a potential bias.

Dependent observations in clinical research.

For many statistical methods that are commonly used in medical research, it is assumed that observations are independent. However, when this assumption is violated, alternative methods may be needed. In this paper, we describe why an analysis that ignores the dependencies within the data may provide biased results and outline possible alternatives. This paper aims to create awareness among researchers, readers, and reviewers for this possible source of bias in medical research.

Real-World Evidence to Inform Regulatory Decision Making: A Scoping Review.

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 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.

Do postoperative hemodynamic parameters add prognostic value for mortality after surgical aortic valve replacement?

Background: Although various hemodynamic parameters to assess prosthetic performance are available, prosthesis-patient mismatch (PPM) is defined exclusively by effective orifice area (EOA) index thresholds. Adjusting for the Society of Thoracic Surgeons predicted risk of mortality (STS PROM), we aimed to explore the added value of postoperative hemodynamic parameters for the prediction of all-cause mortality at 5 years after aortic valve replacement. Methods: Data were obtained from the Pericardial Surgical Aortic Valve Replacement (PERIGON) Pivotal Trial, a multicenter prospective cohort study examining the performance of the Avalus bioprosthesis. Candidate predictors were assessed at the first follow-up visit; patients who had no echocardiography data, withdrew consent, or died before this visit were excluded. Candidate predictors included peak jet velocity, mean pressure gradient, EOA, predicted and measured EOA index, Doppler velocity index, indexed internal prosthesis orifice area, and categories for PPM. The performance of Cox models was investigated using the c-statistic and net reclassification improvement (NRI), among other tools. Results: A total of 1118 patients received the study valve, of whom 1022 were eligible for the present analysis. In univariable analysis, STS PROM was the sole significant predictor of all-cause mortality (hazard ratio, 1.40; 95% confidence interval, 1.26-1.55). When extending the STS PROM with single hemodynamic parameters, neither the c-statistics nor the NRIs demonstrated added prognostic value compared to a model with STS PROM alone. Similar findings were observed when multiple hemodynamic parameters were added. Conclusions: The STS PROM was found to be the main predictor of patient prognosis. The additional prognostic value of postoperative hemodynamic parameters for the prediction of all-cause mortality was limited.

Let's Agree to Disagree on Operative Versus Nonoperative Treatment for Distal Radius Fractures in Older People: Protocol for a Prospective International Multicenter Cohort Study.

BACKGROUND: Distal radius fractures are the most frequently encountered fractures in Western societies, typically affecting patients aged 50 years and older. Although this is a common injury, the best treatment for these fractures in older patients is still under debate. OBJECTIVE: This prospective study aims to compare the outcome of operatively and nonoperatively treated distal radius fractures in the older population. Only patients with distal radius fractures for which equipoise regarding the optimal treatment exists will be included. METHODS: This prospective international multicenter observational cohort study will be designed as a natural experiment. Natural experiments are observational studies in which treatment allocation is determined by factors outside the control of the investigators but also (largely) independent of patient characteristics. Patients aged 65 years and older with an acute distal radius fracture will be considered for inclusion. Treatment allocation (operative vs nonoperative) will be based on the local preferences of the treating hospital either in Switzerland or the Netherlands. Hence, the process governing treatment allocation resembles that of randomization. Patients will be identified after treatment has been initiated. Based on the radiographs and baseline information of the patient, an expert panel of 6 certified trauma surgeons from 2 regions will provide their treatment recommendation. Only patients for whom the experts disagree on treatment recommendations will ultimately be included in the study (ie, for whom there is a clinical equipoise). For these patients, both operative and nonoperative treatment of distal radius fractures are viable, and treatment choice is predominantly determined by personal or local preference. The primary outcome will be the Patient-Rated Wrist Evaluation score at 12 weeks. Secondary outcomes will include the Physical Activity Score for the Elderly, the EQ questionnaire, pain, the living situation, range of motion, complications, and radiological outcomes. By including outcomes such as living situation and the Physical Activity Score for the Elderly, which are not relevant for younger cohorts, valuable information to tailor treatment to the needs of the older population can be gained. According to the sample size collection, which was based on the minimal important clinical difference of the Patient-Rated Wrist Evaluation, 92 patients will have to be included, with at least 46 patients in each treatment group. RESULTS: Enrollment began in July 2023 and is expected to continue until summer 2024. The final follow-up will be 2 years after the last patient is included. CONCLUSIONS: Although many trials on this topic have previously been published, there remains an ongoing debate regarding the optimal treatment for distal radius fractures in older patients. This observational study, which will use a fairly new methodological study design, will provide further information on treatment outcomes for older patients with distal radius fractures for which to date equipoise exists regarding the optimal treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52917.

Transfusion of ever-pregnant donor red blood cells and mortality of male patients.

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from everpregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR] 0.91, 95% confidence interval 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR 1.81, 95% CI 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Comparison of likelihood penalization and variance decomposition approaches for clinical prediction models: A simulation study.

Logistic regression is one of the most commonly used approaches to develop clinical risk prediction models. Developers of such models often rely on approaches that aim to minimize the risk of overfitting and improve predictive performance of the logistic model, such as through likelihood penalization and variance decomposition techniques. We present an extensive simulation study that compares the out-of-sample predictive performance of risk prediction models derived using the elastic net, with Lasso and ridge as special cases, and variance decomposition techniques, namely, incomplete principal component regression and incomplete partial least squares regression. We varied the expected events per variable, event fraction, number of candidate predictors, presence of noise predictors, and the presence of sparse predictors in a full-factorial design. Predictive performance was compared on measures of discrimination, calibration, and prediction error. Simulation metamodels were derived to explain the performance differences within model derivation approaches. Our results indicate that, on average, prediction models developed using penalization and variance decomposition approaches outperform models developed using ordinary maximum likelihood estimation, with penalization approaches being consistently superior over the variance decomposition approaches. Differences in performance were most pronounced on the calibration of the model. Performance differences regarding prediction error and concordance statistic outcomes were often small between approaches. The use of likelihood penalization and variance decomposition techniques methods was illustrated in the context of peripheral arterial disease.

Look left, look right: censoring in clinical research.

In this methodology editorial, the problem of censored survival (or time-to-event) data in clinical research is discussed. In case of censored observations, part of the observation time for some participants in a study is unobserved, which means that measures such as an average survival time cannot be calculated. Instead, censored survival time should explicitly be accounted for in the analysis of a study, for example using the Kaplan-Meier method. Implications of censoring and how to deal with it in the analysis of a study or when reading a research paper are discussed.

Nonoperative treatment of multiple rib fractures, the results to beat: International multicenter prospective cohort study among 845 patients.

BACKGROUND: Optimal treatment (i.e. nonoperative or operative) for patients with multiple rib fractures remains debated. Studies that compare treatments are rationalized by the alleged poor outcomes of nonoperative treatment. METHODS: The aim of this prospective international multicenter cohort study (between January 2018 and March 2021) with one-year follow-up, was to report contemporary outcomes of nonoperatively treated patients with multiple rib fractures. Including 845 patients with three or more rib fractures. Primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (HLOS), (pulmonary) complications, and quality of life. RESULTS: Mean age was 57.7 ± 17.0 years, median Injury Severity Score was 17 (13-22) and the median number of rib fractures was 6 (4-8). In-hospital mortality rate was 1.5% (n = 13), 112 (13.3%) patients had pneumonia and four (0.5%) patients developed a symptomatic non-union. The median HLOS was 7 (4-13) days, and median intensive care unit length of stay was 2 (1-5) days. Mean EQ-5D-5L index value was 0.83 ± 0.18 one year after trauma. Polytrauma patients had a median HLOS of 10 (6-18) days, a pneumonia rate of 17.6% (n = 77) and mortality rate of 1.7% (n = 7). Elderly patients (≥65 years) had a median HLOS of 9 (5-15) days, a pneumonia rate of 19.7% (n = 57) and mortality rate of 4.1% (n = 12). CONCLUSIONS: Overall, nonoperative treatment of patients with multiple rib fractures shows low mortality and morbidity rate and good quality of life after one year. Future studies evaluating the benefit of operative stabilisation should use contemporary outcomes to establish the therapeutic margin of rib fixation. LEVEL OF EVIDENCE: Level III, Therapeutic/Care Management.

Rapid Response to Remdesivir in Hospitalised COVID-19 Patients: A Propensity Score Weighted Multicentre Cohort Study.

INTRODUCTION: Remdesivir is a registered treatment for hospitalised patients with COVID-19 that has moderate clinical effectiveness. Anecdotally, some patients' respiratory insufficiency seemed to recover particularly rapidly after initiation of remdesivir. In this study, we investigated if this rapid improvement was caused by remdesivir, and which patient characteristics might predict a rapid clinical improvement in response to remdesivir. METHODS: This was a multicentre observational cohort study of hospitalised patients with COVID-19 who required supplemental oxygen and were treated with dexamethasone. Rapid clinical improvement in response to treatment was defined by a reduction of at least 1 L of supplemental oxygen per minute or discharge from the hospital within 72 h after admission. Inverse probability of treatment-weighted logistic regression modelling was used to assess the association between remdesivir and rapid clinical improvement. Secondary endpoints included in-hospital mortality, ICU admission rate and hospitalisation duration. RESULTS: Of 871 patients included, 445 were treated with remdesivir. There was no influence of remdesivir on the occurrence of rapid clinical improvement (62% vs 61% OR 1.05, 95% CI 0.79-1.40; p = 0.76). The in-hospital mortality was lower (14.7% vs 19.8% OR 0.70, 95% CI 0.48-1.02; p = 0.06) for the remdesivir-treated patients. Rapid clinical improvement occurred more often in patients with low C-reactive protein (≤ 75 mg/L) and short duration of symptoms prior to hospitalisation (< 7 days) (OR 2.84, 95% CI 1.07-7.56). CONCLUSION: Remdesivir generally does not increase the incidence of rapid clinical improvement in hospitalised patients with COVID-19, but it might have an effect in patients with short duration of symptoms and limited signs of systemic inflammation.

Effects of COVID-19 on diabetes care among dutch diabetes outpatients.

AIMS: The COVID-19 pandemic impacted diabetes care by reducing diabetes outpatient visits and diabetes-related screening due to allocation of healthcare resources. Yet the impact of COVID-19 on diabetes outpatients has not been extensively evaluated. This study aimed to assess the effect of the COVID-19 pandemic on diagnostics and intermediate outcomes of outpatient diabetes care pre- and during COVID. METHODS: This observational cohort study included 8,442 diabetes patients in the Dutch Pediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2019 and 2021. A mixed-effects regression analysis was used to examine differences in target achievement of HbA1c, BMI, blood pressure, LDL-cholesterol, eGFR, and the difference in mean HbA1c between 2019 and 2020 among n = 1,426 outpatients who visited in both years. Analyses were adjusted for age, sex, and BMI. RESULTS: A 22.7% (21.6-23.8%, p < 0.001) decline in outpatient volume was observed during the pandemic (2020). BMI, lipid spectrum, kidney function, and HbA1c were assessed less frequently in 2020 than in 2019. In 2020, compared to 2019, the median HbA1c level increased by 2.2% (1.0 mmol/mol, p = 0.035) and the percentages of patients with known HbA1C meeting targets below 10, 8, 7% (86, 64, and 53 mmol/mol) decreased by 0.5%, 1.7% and 1.4%, respectively. Target blood pressure ≤ 130/80 mmHg was achieved more often in 2020 (15.0% versus 18.3%, p = 0.018), while HbA1c ≤ 86 mmol/mol was achieved less (89.3% versus 87.1%, p = 0.001), among diabetes outpatients seen in both 2019 and 2020. In patients visiting both years, HbA1c was 2.3% (1.9 mmol/l, 95% CI 1.2-2.5, p < 0.001) lower during the pandemic than in the prepandemic (2019). CONCLUSIONS: The COVID pandemic was associated with a marked reduction in patient volume in diabetes outpatient care among five hospitals. Among patients who received outpatient care both before and during the pandemic period, HbA1c control and blood pressure control enhanced during the pandemic. Re-evaluation of current diabetes outpatient care organization is warranted to ensure optimal diabetes care in future times.

[Treatment of traumatic rib fractures]. / Behandeling van traumatische ribfracturen.

Patients with rib fractures are a heterogenous group of patients who are treated by general practitioners as well as by specialized trauma surgeons. We present three patients with rib fractures with different degrees of thoracic trauma and therefore treatments differ significantly. The cornerstone in the treatment of rib fractures remains attaining adequate analgesia and breathing exercises. The last decade, there has been an increase in the utilization of rib fixation, however, precise indications remain unknown. It has proven effective in patients with flail chest on mechanical ventilation in whom it decrease intensive care and hospital length and reduces mortality. In case of prolonged (> 3 months) pain, dyspnea or a clicking sensation one could think of a nonunion of the rib fracture. Rib fixation can relieve these complaints in about 60% of the patients, however due to a high implant irritation rate and secondary operation to remove the osteosynthesis is common.

Dynamics in cardiac surgery: trends in population characteristics and the performance of the EuroSCORE II over time.

OBJECTIVES: The aim of this study was to investigate the performance of the EuroSCORE II over time and dynamics in values of predictors included in the model. METHODS: A cohort study was performed using data from the Netherlands Heart Registration. All cardiothoracic surgical procedures performed between 1 January 2013 and 31 December 2019 were included for analysis. Performance of the EuroSCORE II was assessed across 3-month intervals in terms of calibration and discrimination. For subgroups of major surgical procedures, performance of the EuroSCORE II was assessed across 12-month time intervals. Changes in values of individual EuroSCORE II predictors over time were assessed graphically. RESULTS: A total of 103 404 cardiothoracic surgical procedures were included. Observed mortality risk ranged between 1.9% [95% confidence interval (CI) 1.6-2.4] and 3.6% (95% CI 2.6-4.4) across 3-month intervals, while the mean predicted mortality risk ranged between 3.4% (95% CI 3.3-3.6) and 4.2% (95% CI 3.9-4.6). The corresponding observed:expected ratios ranged from 0.50 (95% CI 0.46-0.61) to 0.95 (95% CI 0.74-1.16). Discriminative performance in terms of the c-statistic ranged between 0.82 (95% CI 0.78-0.89) and 0.89 (95% CI 0.87-0.93). The EuroSCORE II consistently overestimated mortality compared to observed mortality. This finding was consistent across all major cardiothoracic surgical procedures. Distributions of values of individual predictors varied broadly across predictors over time. Most notable trends were a decrease in elective surgery from 75% to 54% and a rise in patients with no or New York Heart Association I class heart failure from 27% to 33%. CONCLUSIONS: The EuroSCORE II shows good discriminative performance, but consistently overestimates mortality risks of all types of major cardiothoracic surgical procedures in the Netherlands.

Mobile health for cardiovascular risk management after cardiac surgery: results of a sub-analysis of The Box 2.0 study.

Aims: Lowering low-density lipoprotein (LDL-C) and blood pressure (BP) levels to guideline recommended values reduces the risk of major adverse cardiac events in patients who underwent coronary artery bypass grafting (CABG). To improve cardiovascular risk management, this study evaluated the effects of mobile health (mHealth) on BP and cholesterol levels in patients after standalone CABG. Methods and results: This study is a post hoc analysis of an observational cohort study among 228 adult patients who underwent standalone CABG surgery at a tertiary care hospital in The Netherlands. A total of 117 patients received standard care, and 111 patients underwent an mHealth intervention. This consisted of frequent BP and weight monitoring with regimen adjustment in case of high BP. Primary outcome was difference in systolic BP and LDL-C between baseline and value after three months of follow-up. Mean age in the intervention group was 62.7 years, 98 (88.3%) patients were male. A total of 26 449 mHealth measurements were recorded. At three months, systolic BP decreased by 7.0 mmHg [standard deviation (SD): 15.1] in the intervention group vs. -0.3 mmHg (SD: 17.6; P < 0.00001) in controls; body weight decreased by 1.76 kg (SD: 3.23) in the intervention group vs. -0.31 kg (SD: 2.55; P = 0.002) in controls. Serum LDL-C was significantly lower in the intervention group vs. controls (median: 1.8 vs. 2.0 mmol/L; P = 0.0002). Conclusion: This study showed an association between home monitoring after CABG and a reduction in systolic BP, body weight, and serum LDL-C. The causality of the association between the observed weight loss and decreased LDL-C in intervention group patients remains to be investigated.

Subgroup analyses in clinical research: too tempting?

In many biomedical studies, subgroup analyses are performed to identify subgroups of patients in whom a treatment is most effective, or a risk factor has the largest effect. While both are referred to as subgroup analysis, it is important to distinguish between the estimation of effects within subgroups and the comparison of effects across subgroups. Both are discussed, and we outline the implications regarding sample size and statistical methods for estimation of effects. Also, the risk of false-positive findings-which potentially increases with subgroup analysis-is discussed, as well as the distinction between effect modification and interaction.

Unintended impact of pharmacovigilance regulatory interventions: A systematic review.

AIMS: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. METHODS: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. RESULTS: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). CONCLUSION: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.