Abstract Hereditary spherocytosis (HS) is a hereditary hemolytic anemia with limited treatment options. A relative decrease in the activity of pyruvate kinase (PK), an essential glycolytic enzyme in red blood cells (RBCs), has been described in patients with HS. Owing to their dependence on glycolysis, PK activation therapy could therefore potentially improve red cell health in HS. This study aimed to evaluate PK activity in HS RBCs and to investigate the effect of 2 PK activators (mitapivat and tebapivat). Blood samples from 18 patients with non-transfusion-dependent HS (splenectomized and nonsplenectomized) were analyzed. Our results confirmed impaired glycolysis in HS at baseline, indicated by a relatively decreased PK activity (PK-to-hexokinase ratio, 7.6 in HS vs 11.4 in controls). PK activity (increase >50%) and adenosine triphosphate levels (increase >44%) improved upon ex vivo treatment with mitapivat and tebapivat. Metabolomics showed various metabolic alterations upon treatment. Furthermore, the hydration state of the cells improved (Ohyper increase >2.1%). No improvements were found in deformability, intracellular calcium, and cellular adhesion to laminin. When comparing splenectomized patients with nonsplenectomized patients, we found that PK thermostability in nonsplenectomized patients was decreased more than in splenectomized patients. After this, PK activator therapy improved PK thermostability to a greater extent in RBCs from splenectomized patients, which seems to relate to the degree of reticulocytosis. Overall, we demonstrated that PK activation improves the metabolic and cellular properties of HS RBCs ex vivo, supporting the rationale for further evaluation of PK activation in HS.

Cognitive impairment is common in patients with heart failure, but to which extent cognitive complaints are evaluated and listed in clinical practice is unknown. Therefore, this study aims to identify whether cognitive complaints are listed in clinical notes of patients with heart failure, consistent with listed complaints in clinical notes of patients attending memory clinics, by using natural language processing (NLP) techniques. Patients with heart failure and patients attending a memory outpatient clinic were identified by using echocardiography reports and presence of memory outpatient clinic codes stored in the Utrecht Individual-Oriented Database (UPOD) from 2011 to 2023. Named Entity Detection and Linking (NER+L) strategies MedCAT and MedCATTrainer were used to extract listed complaints in clinical notes by patient group, and it was assessed whether cognitive complaints were listed in clinical notes of patients with heart failure. Among 5803 patients with heart failure, dyspnea (57.1%), chest pain (48.4%), and oedema (43.6%) were the most listed complaints. In 967 patients attending memory clinics, memory problem (80.9%), getting lost (24.1%), and being morose (22.5%) were the most listed complaints. Notably, in patients with heart failure, the reporting of memory problems was low at 2.6%. This study shows a low reporting frequency of cognitive complaints in clinical notes of patients with heart failure, even though both conditions often co-occur according to cross-sectional studies. This points towards a potential underrecognition of cognitive complaints in patients with heart failure during clinical practice. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is part of the Heart-Brain Connection crossroads (HBCx) consortium of the Dutch CardioVascular Alliance (DCVA). HBCx has received funding from the Dutch Heart Foundation under grant agreements 201828 and CVON 201206. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics of our study was reviewed by the Medical Ethics Committee NedMec (METC NedMec). METC NedMec is a recognized Medical Research Ethics Committee in the Netherlands, formed through a collaboration between UMC Utrecht, Prinses Máxima Centrum for pediatric oncology, and the Antoni van Leeuwenhoek institute. As our research involves retrospective analysis of electronic health records (EHR) and does not fall under the scope of the Dutch Medical Research Involving Human Subjects Act (WMO), the committee determined that formal ethical approval was not required (waived). Furthermore, in line with GDPR Article 14(5)(b), individual patient consent was not required due to the disproportionate effort involved in contacting all individuals. Data management specialists from an ISO 9001 certified database (Utrecht Patient-Oriented Database) extracted, pseudonymized and securely stored the data. As we worked with electronic health records collected with an IRB waiver for informed consent from NedMec, under the disproportionate effort clause, I will not be able to share data with others. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes s we worked with electronic health records collected with an IRB waiver for informed consent from NedMec, under the disproportionate effort clause, I will not be able to share data with others.

BACKGROUND:The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)ASR-NB2009 estimated glomerular filtration rate (eGFR) equation has shown substantial overestimation of GFR in Europeans, hence new equations have been developed. We examined the effect of introducing the European Kidney Function Consortium (EKFC) or Lund-Malmö revised (LMR) eGFR equations on KDIGO eGFR category classification in a large cohort. We compared the EKFC and LMR equations with the CKD-EPIASR-NB2009 formula in view of discriminative ability of all-cause mortality, kidney failure with replacement therapy (KFRT) and acute kidney injury (AKI) risks across eGFR categories. METHODS:Individuals aged ≥18 years with a serum creatinine measurement (December 2006-July 2024) at University Medical Center Utrecht, were included. Hazard ratios (HRs) were analysed for all outcomes per eGFR category, per equation. Harrell's Concordance index (C-index) was used to assess the ability of risk discrimination across eGFR categories. Whether reclassification between eGFR categories was justified by the occurrence of events, was assessed with net reclassification improvement analysis. RESULTS:In total, 285 686 individuals were included. Compared with the CKD-EPIASR-NB2009 equation, the EKFC and LMR estimated GFR lower [mean -6.3 (standard deviation, SD 5.3) and -10.7 (SD 6.5) mL/min/1.732, respectively]. The number of individuals with eGFR <60 mL/min/1.73 m2 increased 29.0% (EKFC) and 36.4% (LMR). The EKFC predominantly reclassified older individuals, and the LMR older men, to worse eGFR categories. HRs of reclassified individuals to worse eGFR categories were mainly higher compared with the non-reclassified. The EKFC and LMR equations showed equal/improved C-index for mortality (EKFC 0.584/LMR 0.588/CKD-EPIASR-NB2009 0.570), KFRT (0.895/0.900/0.897) and AKI (0.606/0.609/0.599). The LMR equation reclassified more individuals without an event to worse eGFR categories. CONCLUSION:eGFR category classification was substantially different when using the EKFC or LMR equation compared with the CKD-EPIASR-NB2009 formula. Both equations showed equal to improved ability of risk stratification across eGFR categories. Shifts in eGFR category classification might significantly impact clinical decisions. Given that we have identified variation between equations, a careful consideration of the advantages and disadvantages of different eGFR equations is essential.

Objective During the COVID-19 pandemic, a substantial decrease was observed in hospital admissions and in-hospital procedures for patients with acute cardiovascular diseases (CVDs). The extent to which measures to prevent COVID-19 transmission, for example, lockdowns, affected the outpatient care of patients at higher cardiovascular risk remains unclear. We aimed to compare outpatient department (OPD) attendance, cardiovascular risk management (CVRM) and cardiovascular health (CVH) of patients at higher cardiovascular risk referred to an OPD of a tertiary care centre between preCOVID-19, during and postCOVID-19 periods.Design, setting and participants We included all adult patients at higher cardiovascular risk referred to the cardiology, vascular medicine, diabetology, geriatrics, nephrology or multidisciplinary vascular surgery OPDs of the University Medical Centre Utrecht, the Netherlands, between March 2019 and December 2022, in a prospective cohort study.Main outcome measures We assessed trends in the number of first and follow-up appointments and in the completeness of extractable CVRM indicators from the electronic health record (EHR) as a proxy for CVRM guideline adherence. CVH was determined using the Life’s Essential 8 metric (score 0–100, the higher score, the better). We investigated whether CVH differed between COVID-19 periods compared with the reference period (ie, 2019) and stratified by OPDs, using multivariable linear regression, adjusted for age, gender, CVD history and whether the patient had a previous appointment before the reference period.Results Among 15 143 patients, we observed a 33% reduction in the weekly number of first appointments during the COVID-19 pandemic, with the largest reductions in the cardiology and nephrology OPDs, with no differences between women and men. Follow-up appointments conducted remotely, compared with before the COVID-19 pandemic, increased significantly for all OPDs. CVRM indicators were up to 11% less extractable during the first lockdown yet returned to prepandemic levels directly after the first lockdown period. The CVH score of patients visiting the nephrology, vascular medicine and geriatrics OPDs during the first lockdown was 11.23 (95% CI 2.74 to 19.72), 5.68 (95% CI 0.82 to 10.54) and 5.66 (95% CI 0.01 to 11.31) points higher, respectively, compared with the prepandemic period. In between the second and third lockdowns, the CVH score was comparable to the preCOVID reference period, yet for the cardiology OPD it was significantly higher (5.54, 95% CI 2.04 to 9.05).Conclusions During the COVID-19 pandemic, weekly numbers of first appointments to OPDs decreased, and a population with a higher CVH score (ie, better CVH) visited certain OPDs, especially during the first lockdown period. These suggest that patients with poorer CVH more often avoided or were unable to visit OPDs, which might have resulted in missed opportunities to control cardiovascular risk factors and potentially may have led to preventable disease outcomes. For future epidemics and pandemics, it seems vital to develop a strategy that includes an emphasis on seeking healthcare when needed, with specific attention to patients at higher CVD risk.

Background The routine diagnostic process increasingly entails the processing of high-volume and high-dimensional data that cannot be directly visualised. This processing may provide scaling issues that limit the implementation of these types of data into research as well as integrated diagnostics in routine care. Here, we investigate whether we can use existing dimension reduction techniques to provide visualisations and analyses for a complete bloodcount (CBC) while maintaining representativeness of the original data. We considered over 3 million CBC measurements encompassing over 70 parameters of cell frequency, size and complexity from the UMC Utrecht UPOD database. We evaluated PCA as an example of a linear dimension reduction techniques and UMAP, TriMap and PaCMAP as non-linear dimension reduction techniques. We assessed their technical performance using quality metrics for dimension reduction as well as biological representation by evaluating preservation of diurnal, age and sex patterns, cluster preservation and the identification of leukemia patients. Results We found that, for clinical hematology data, PCA performs systematically better than UMAP, TriMap and PaCMAP in representing the underlying data. Biological relevance was retained for periodicity in the data. However, we also observed a decrease in predictive performance of the reduced data for both age and sex, as well as an overestimation of clusters within the reduced data. Finally, we were able to identify the diverging patterns for leukemia patients after use of dimensionality reduction methods. Conclusions We conclude that for hematology data, the use of unsupervised dimension reduction techniques should be limited to data visualization applications, as implementing them in diagnostic pipelines may lead to decreased quality of integrated diagnostics in routine care.

Background:Medical resource allocation is important to ensure availability of care, especially in challenging circumstances like a pandemic. In fields of unpredictable care demand such as obstetrics, forecasting may help manage scarce resources. Objective:The development, validation, and implementation of a regional birth forecasting tool to support obstetrical staff planning in the Utrecht region during the COVID-19 pandemic. Methods:We combined predicted birth dates retrieved from Saltro, a large regional primary care laboratory, with data from the Dutch national perinatal registry (Perined) and Statistics Netherlands for model development. We created and implemented an HTML tool visualizing these forecasts, which were discussed during the regional acute obstetric health care network meetings. Six months after implementation, we assessed the impact of the tool using an evaluative stakeholder meeting. Results:We achieved a performance accuracy (R) of 0.45, 0.61, and 0.67 (all actual number of births within 95% CI) forecasting the number of births in the region, pooled in 1-, 2-, and 3-weekly bins, respectively. After presenting these findings to stakeholders, we implemented a forecasting tool using the 2-week bin model. The evaluative stakeholder meeting proved that the tool improved communication, awareness of health care need, and collaborations among health care providers in the Utrecht region. Additionally, stakeholders identified additional applications, such as communication with patients and training of obstetric health care providers. Conclusions:Implementation of a forecasting tool for the number of births based on available data across the health care system added value to obstetrical care by providing insight into care demand, and increasing communication, awareness, and collaboration between health care providers. Further research should aim at improving regional obstetric acute care by fostering data sharing in order to improve health care demand forecasts.

BACKGROUND:Acute kidney injury (AKI) is associated with increased risks of incidence or progression of chronic kidney disease (CKD), kidney failure (KF), or major adverse kidney events (MAKE), however, it remains unclear which individuals have higher risks. Hence, we systematically reviewed the literature to explore differences in kidney dysfunction risks between AKI stages, AKI durations, and clinical settings. METHODS:We performed a systematic search in PubMed and Embase to identify studies that examined at least one outcome of interest in individuals with AKI versus without AKI, with a minimum follow-up of one year. Hazard/odds ratios (HR/OR) were pooled using random effects models. Heterogeneity across patient and disease characteristics was examined using subgroup and meta-regression analyses. RESULTS:We searched 70 studies, encompassing 1 838 668 individuals, including 165 715 with AKI. All studies were of moderate to high quality. Individuals with AKI had higher risks of CKD incidence [AKI 25.8%/no AKI 8.7%; HR 2.36 [95% confidence interval (CI) 1.77-2.94)]], CKD progression [AKI 43.1%/no AKI 35.6%; HR 1.83 (95%CI 1.26-2.40)], KF [AKI 2.9%/no AKI 0.5%; HR 2.64 (95%CI 2.03-3.25)], and MAKE [AKI 59.0%/no AKI 32.7%; OR 2.77 (95%CI 2.01-3.53)]. The pooled effect estimates for CKD incidence after AKI lasting <3 days remained significant [OR 2.37 (95%CI 1.68-3.07)], even in individuals with AKI stage 1 only [HR 1.49 (95%CI 1.44-1.55)]. Diabetes mellitus, hypertension, requiring acute dialysis, cardiovascular surgery, or coronary artery disease were associated with higher CKD incidence or progression risks. CONCLUSIONS:Risks for kidney dysfunction were higher for all individuals with AKI. Risk estimates were heterogeneous between patient subgroups, based on AKI stage, AKI duration, and clinical setting, yet even individuals with the lowest stage or shortest duration of AKI remained at higher risk for CKD incidence or progression. This highlights the need to develop tailored follow-up strategies to recognize kidney function decline post-AKI and initiate kidney protective measures in a timely fashion.

With the digitization of health records, the reuse of Electronic Health Record (EHR) data has become increasingly prevalent in research. Using blood pressure as a case study, this paper examines the complexities and practical realities of reusing EHR data, emphasizing the importance of contextual information for accurate interpretation. Although blood pressure data derived from EHR systems may appear straightforward—often captured by machines or derived from standardized workflows—their reuse is frequently complicated by variability in measurement methods and clinical contexts, which can produce seemingly similar but clinically distinct blood pressure readings. The paper begins with the physiology of blood pressure and the various techniques used to measure it. This is followed by an analysis of different clinical settings—i.e., the different pathophysiological situations—that may affect both measurement practices and data interpretation. The paper then explores how these measurements are recorded in EHR systems and concludes with practical guidance to support researchers in identifying blood pressure data that are truly fit for the intended research purpose. By acknowledging the inherent complexities of healthcare data and making informed data selection decisions, researchers can better harness the potential of EHRs to generate meaningful insights that ultimately improve patient care.

Abstract Background and Aims Little is known about which patients to follow-up after an episode of acute kidney injury (AKI) for future risks. The aim of this review is to assess the association between AKI and the incidence or progression of chronic kidney disease (CKD) or end-stage kidney disease (ESKD), stratified by subcategories of AKI-stages, -durations, and clinical settings. Method A systematic search of the literature in PubMed and Embase was performed by two reviewers to identify studies that examined CKD incidence (development of CKD stage ≥3), CKD progression (worsening of kidney function in patients with CKD stage ≥3), or ESKD, in patients with AKI versus patients without AKI. The risk of bias was assessed using the Newcastle-Ottawa Scale. Relative effect estimates (odds and hazard ratios) were pooled using a random effects model. Results In total, 48 retrospective and 13 prospective studies, encompassing 140.985 patients with AKI, were included in this review. All the studies were of moderate or high quality. The pooled effect ratio was 3.36 (95% confidence interval (CI) 2.68-4.03) for CKD incidence (n = 31 studies). This remained 3.40 (95% CI 1.79-5.00) in a sub analysis including patients with a recovered kidney function post-AKI, and 1.49 (95% CI 1.44-1.55) in a sub analysis including patients with an AKI lasting less than 3 days (Fig. 1). Overall, the effect ratio for CKD progression (n = 11 studies) was 1.70 (95% CI 1.38-2.01) and 3.81 (95% CI 2.58-5.04) for ESKD (n = 24 studies). The increased risk of these two outcomes were not seen in the sub analyses only including patients with AKI lasting less than 3 days. Overall, there is an observable higher risk for CKD incidence, CKD progression, and ESKD with increased AKI staging, although not always statistically significant. Minimal variations were observed across clinical settings. Conclusion In our review, including over 60 studies, we found that AKI was associated with an increased risk of CKD incidence, CKD progression, and ESKD. Patients with higher AKI-stages had even larger risks. Notably, even brief episodes of AKI (lasting less than 3 days) were associated with a higher risk of CKD incidence compared to patients without AKI. In contrary, the risk for ESKD is not enlarged in a sub analysis including patients with recovered kidney function compared to patients without AKI. These result warrant close monitoring of the kidney function post-AKI, specifically in patients with AKI lasting 3 days or longer. Future research should focus more on the risk of CKD progression in order to tailor follow-up care in these more vulnerable patients.

Background: Red blood cells (RBCs) are biconcave-shaped cells with viscoelastic membranes optimally adapted for oxygen delivery and gas exchange. RBCs have the antioxidant capacity to protect against reactive oxygen species (ROS). If this capacity is exceeded, damage can be inflicted, which disrupts cellular deformability, structure, and membrane properties. Sickle cell disease (SCD) is a monogenetic disorder characterized by RBCs that deform from biconcave to typically sickle-shaped upon deoxygenation, leading to reduced deformability. SCD-RBCs suffer from high levels of oxidative stress, which may exhaust their physiological antioxidant capacity. Therefore, there is a need for biomarkers to evaluate differences in withstanding oxidative stress among patients and to monitor treatment response. Aim: To evaluate the key parameters of RoxyScan as novel biomarkers that reflect the ability of SCD RBCs to withstand oxidative stress. Methods: Patients with HbSS, HbSβ0, HbSβ+, or HbSC were eligible to participate in the study. Patients who received blood transfusions <3 months before blood collection were excluded. RoxyScan was used to assess susceptibility to oxidative stress. This novel application of Lorrca (RR Mechatronics, Zwaag) measures the deformability of RBCs in response to exposure to cumene hydroperoxide (CHP, 90µM) during continuous shear (30 Pa). T-POD was defined as the time (seconds) required to reach a 10% decrease in deformability (expressed as EI, Elongation Index), calculated from a fitted curve. EIMin was characterized by the minimum elongation index reached during the assay. RoxyScan parameters were correlated to RBC sickling tendency (Point of Sickling, PoS, assessed by oxygen gradient ektacytometry), complete blood count (Cell Dyn Sapphire, Abbott), hemolysis markers and hemoglobin subfractions (HbF/HbS/HbSC) (HPLC, Tosoh G8). Additionally, ex vivo treatment with l-glutamine (2mM, 1h) was performed and evaluated using RoxyScan. Results: Fifty adult SCD patients (HbSS/Sβ0, N=26; HbSC, N=20; HbSβ+ N=4) and 21 healthy controls (HC) were included. HbSS/Sβ0 and HbSC RBCs showed a significantly lower T-POD than HC, indicating a faster deformability loss in response to the same level of oxidant exposure (HC 1739s (SD 238s), HbSS/Sβ0 776s (SD 328s), HbSC: 1031s (SD 225s)). HbSC RBCs showed substantially more pronounced homogeneity in the response. When correlating T-POD to hemolysis parameters in HbSS/Sβ0, a trend of inverse correlation with reticulocyte count (p=0,09), lactate dehydrogenase (LDH, p=0,10), and bilirubin (p=0,068) was found. Furthermore, T-POD was significantly correlated with PoS in HbSS/Sβ0 patients, showing a direct link between RBC sickling tendency and ability to withstand oxidative stress. No significant T-POD correlations with sickling and hemolysis parameters were observed in patients with HbSC. Ex vivo treatment with l-glutamine showed a significant improvement in T-POD and EIMin despite substantial variation in individual patient responses. Conclusion: In this study, we demonstrated the applicability of RoxyScan as a novel method for assessing the susceptibility of RBCs to oxidative stress in SCD. Patients with HbSS/Sβ0 and HbSC showed an earlier and more pronounced loss of deformability than HC did. Furthermore, correlations between T-POD and laboratory parameters in HbSS/Sβ0 patients compared to HbSC patients demonstrated different characteristics in terms of oxidative stress. The results of l-glutamine experiments showed the benefit of RoxyScan in evaluating treatment response and could help to identify patients benefiting from treatment with l-glutamine. Future studies are needed to explore the clinical applicability of RoxyScan.

Background: Between 2002 and 2011, the incidence of severe primary postpartum hemorrhage (PPH) in Dutch women with von Willebrand disease (VWD) and hemophilia carriers (HCs) was 8% vs 4.5% in the general population. Objectives: To determine the contemporary incidence of severe primary PPH in women with VWD and HCs. Methods: All women with VWD or HCs who delivered between 2012 and 2017 were selected from all 6 Dutch hemophilia treatment centers. Data on patient and disease characteristics, peripartum hematologic and obstetric management, and outcomes were retrospectively collected. Incidence of severe primary (>= 1000 mL of blood loss <= 24 hours after childbirth) and primary (>= 500 mL within <= 24 hours after childbirth) PPH was compared with the (1) previous cohort and (2) general Dutch population and between (3) women with VWD and HCs with third-trimester coagulation activity levels <50 international units (IU)/dL vs >= 50 IU/dL and (4) women treated with vs without peripartum hemostatic prophylaxis. Results: Three-hundred forty-eight deliveries (151 VWD, 167 hemophilia A, and 30 hemophilia B carriers) were included. The severe primary PPH incidence was 10% (36/ 348) and remained stable over time, whereas this incidence has increased in the general population (to 8%), leading to a similar risk (P = .17). Severe primary PPH risk was comparable between women with coagulation activity levels <50 and >= 50 IU/dL (11% [7/66] vs 10% [29/279]; odds ratio, 1.02; 95% CI, 0.43-2.44) and comparable between those with and those without prophylaxis (12% [11/91] vs 10% [25/254]; odds ratio, 1.26; 95% CI, 0.59-2.68). Conclusion: Severe primary PPH in women with VWD and HCs remained stable and is comparable with the increasing prevalence in the general population. More research is needed to find the optimal pregnancy management strategy for safe delivery in VWD and HC.

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p < 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p < 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.

Abstract The most common forms of sickle cell disease (SCD) are sickle cell anemia (SCA; HbSS) and HbSC disease. In both, especially the more dense, dehydrated and adherent red blood cells (RBCs) with reduced deformability are prone to hemolysis and sickling, and thereby vaso‐occlusion. Based on plasma amino acid profiling in SCD, a composition of 10 amino acids and derivatives (RCitNacQCarLKHVS; Axcella Therapeutics, USA), referred to as endogenous metabolic modulators (EMMs), was designed to target RBC metabolism. The effects of ex vivo treatment with the EMM composition on different RBC properties were studied in SCD (n = 9 SCA, n = 5 HbSC disease). Dose‐dependent improvements were observed in RBC hydration assessed by hemocytometry (MCV, MCHC, dense RBCs) and osmotic gradient ektacytometry (Ohyper). Median (interquartile range [IQR]) increase in Ohyper compared to vehicle was 4.9% (4.0%–5.5%), 7.5% (6.9%–9.4%), and 12.8% (11.5%–14.0%) with increasing 20×, 40×, and 80X concentrations, respectively (all p < 0.0001). RBC deformability (EImax using oxygen gradient ektacytometry) increased by 8.1% (2.2%–12.1%; p = 0.0012), 9.6% (2.9%–15.1%; p = 0.0013), and 13.3% (5.7%–25.5%; p = 0.0007), respectively. Besides, RBC adhesion to subendothelial laminin decreased by 43% (6%–68%; p = 0.4324), 58% (48%–72%; p = 0.0185), and 71% (49%–82%; p = 0.0016), respectively. Together, these results provide a rationale for further studies with the EMM composition targeting multiple RBC properties in SCD.

BackgroundClinical decision support systems (CDSSs) based on routine care data, using artificial intelligence (AI), are increasingly being developed. Previous studies focused largely on the technical aspects of using AI, but the acceptability of these technologies by patients remains unclear. ObjectiveWe aimed to investigate whether patient-physician trust is affected when medical decision-making is supported by a CDSS. MethodsWe conducted a vignette study among the patient panel (N=860) of the University Medical Center Utrecht, the Netherlands. Patients were randomly assigned into 4 groups—either the intervention or control groups of the high-risk or low-risk cases. In both the high-risk and low-risk case groups, a physician made a treatment decision with (intervention groups) or without (control groups) the support of a CDSS. Using a questionnaire with a 7-point Likert scale, with 1 indicating “strongly disagree” and 7 indicating “strongly agree,” we collected data on patient-physician trust in 3 dimensions: competence, integrity, and benevolence. We assessed differences in patient-physician trust between the control and intervention groups per case using Mann-Whitney U tests and potential effect modification by the participant’s sex, age, education level, general trust in health care, and general trust in technology using multivariate analyses of (co)variance. ResultsIn total, 398 patients participated. In the high-risk case, median perceived competence and integrity were lower in the intervention group compared to the control group but not statistically significant (5.8 vs 5.6; P=.16 and 6.3 vs 6.0; P=.06, respectively). However, the effect of a CDSS application on the perceived competence of the physician depended on the participant’s sex (P=.03). Although no between-group differences were found in men, in women, the perception of the physician’s competence and integrity was significantly lower in the intervention compared to the control group (P=.009 and P=.01, respectively). In the low-risk case, no differences in trust between the groups were found. However, increased trust in technology positively influenced the perceived benevolence and integrity in the low-risk case (P=.009 and P=.04, respectively). ConclusionsWe found that, in general, patient-physician trust was high. However, our findings indicate a potentially negative effect of AI applications on the patient-physician relationship, especially among women and in high-risk situations. Trust in technology, in general, might increase the likelihood of embracing the use of CDSSs by treating professionals.

Introduction Heart failure (HF) and cognitive impairment (CI) are prevalent and often co-occurring conditions, affecting a considerable portion of the population. Hemodynamic disturbances are important but do not fully explain CI. Therefore, novel etiological insights are needed to clarify the heart-brain axis. This study focuses on unraveling mechanisms underlying cognitive decline in HF patients. We hypothesized that we could identify symptom commonalities extracted from real- world clinical anamnesis texts of patients with HF and CI using text-mining procedures. This may lead to novel mechanistic clues on cognitive decline in patients with HF and could provide potential leads for future treatment trials. Methods In this study, we analyzed anamnesis texts of HF and CI patients between 2011 and 2023 using electronic health records (EHRs) from the Utrecht Patient-Oriented Database (UPOD). Patients with HF and CI were identified through text mining of echocardiogram reports and the presence of clinical neurological and geriatric reports from outpatient memory clinics, respectively. To investigate noted symptomatic overlap in HF and CI, we utilized Named Entity Detection and Linking (NER+L) strategies to link noted symptoms in anamnesis texts with three Dutch biomedical ontologies. Results In total, anamnesis texts of 5597 unique HF and 961 CI patients were extracted and analyzed. Top-3 reported symptoms in HF patients were dyspnea (71.3%), hydrops (47.1%), and dizziness (43.6%) (Figure 2). Top-3 reported symptoms in CI patients were memory impairment (55.5%), cognitive problems (54.2%), and getting lost (21.1%). The noted symptoms that overlapped between HF and CI patients were fear, dizziness, tiredness, uncertain behavior, appetite, headache, and lack of energy. We did not find any noted cognitive symptoms in HF patients' anamnesis texts, nor did we find any noted cardiac symptoms in CI patients. Discussion Based on real-world evidence, we identified noted overlap in reported symptoms in HF and CI. These symptoms could be potential leads for future treatment trials.

Abstract Background and Aims Quantifying the kidney function is crucial for diagnosing and monitoring kidney disorders in clinical practice. Recently, the CKD-EPI 2021 formula was developed for estimating glomerular filtration rate (eGFR), excluding the ethnicity variable. In this study, we aimed to analyze the impact in a Dutch routine-care cohort of introducing the new serum creatinine-based CKD-EPI 2021 formula on glomerular kidney function estimation and the prevalence of chronic kidney disease (CKD), compared to the now used CKD-EPI 2012 formula. Method All patients of 18 years and older of whom serum creatinine was measured between January 2013 and December 2023 at the University Medical Center Utrecht in the Netherlands, were included. Differences in the eGFR measured with the CKD-EPI 2012 formula and the new CKD-EPI 2021 formula were defined as median difference, stratified by gender, age categories, and CKD stages. Results 251.960 patients with 2.312.313 serum creatinine measurements were included in our analysis. Our findings indicate that the CKD-EPI 2021 formula results in a higher eGFR compared to the CKD-EPI 2012 formula (median +3.6 (Inter quartile range (IQR) 2.4 to 4.5) ml/min/1.73 m2 in men, and median +3.1 (IQR 2.0 to 4.0) ml/min/1.73 m2 in women). In total, 21.1% of the patients with CKD stage 2-5 according to the CKD-EPI 2012 formula were classified as having a better CKD stage using the new CKD-EPI 2021 formula; 26.1%, 20.5%, and 15.1% of the patients classified as having CKD stage 3A, 3B, and 4 were classified as having CKD stage 2, 3A, and 3B, respectively (Table 1). Conclusion The introduction of the CKD-EPI 2021 formula would have significant implications for kidney function estimation in the Dutch clinical setting. It is crucial to consider these differences when interpreting kidney function data and making clinical decisions, especially given the potential impact on diagnosing CKD and dosing medication.

Objective Acute kidney injury (AKI) is easily missed and underdiagnosed in routine clinical care. Timely AKI management is important to decrease morbidity and mortality risks. We recently implemented an AKI e-alert at the University Medical Center Utrecht, comparing plasma creatinine concentrations with historical creatinine baselines, thereby identifying patients with AKI. This alert is limited to data from tertiary care, and primary care data can increase diagnostic accuracy for AKI. We assessed the added value of linking primary care data to tertiary care data, in terms of timely diagnosis or excluding AKI. Methods With plasma creatinine tests for 84,984 emergency department (ED) visits, we applied the Kidney Disease Improving Global Outcome guidelines in both tertiary care-only data and linked data and compared AKI cases. Results Using linked data, the presence of AKI could be evaluated in an additional 7886 ED visits. Sex- and age-stratified analyses identified the largest added value for women (an increase of 4095 possible diagnoses) and patients ≥60 years (an increase of 5190 possible diagnoses). We observed 398 additional visits where AKI was diagnosed, as well as 185 cases where AKI could be excluded. We observed no overall decrease in time between baseline and AKI diagnosis (28.4 days vs. 28.0 days). For cases where AKI was diagnosed in both data sets, we observed a decrease of 2.8 days after linkage, indicating a timelier diagnosis of AKI. Conclusions Combining primary and tertiary care data improves AKI diagnostic accuracy in routine clinical care and enables timelier AKI diagnosis.

BackgroundElectronic informed consent (eIC) is increasingly used in clinical research due to several benefits including increased enrollment and improved efficiency. Within a learning health care system, a pilot was conducted with an eIC for linking data from electronic health records with national registries, general practitioners, and other hospitals. ObjectiveWe evaluated the eIC pilot by comparing the response to the eIC with the former traditional paper-based informed consent (IC). We assessed whether the use of eIC resulted in a different study population by comparing the clinical patient characteristics between the response categories of the eIC and former face-to-face IC procedure. MethodsAll patients with increased cardiovascular risk visiting the University Medical Center Utrecht, the Netherlands, were eligible for the learning health care system. From November 2021 to August 2022, an eIC was piloted at the cardiology outpatient clinic. Prior to the pilot, a traditional face-to-face paper-based IC approach was used. Responses (ie, consent, no consent, or nonresponse) were assessed and compared between the eIC and face-to-face IC cohorts. Clinical characteristics of consenting and nonresponding patients were compared between and within the eIC and the face-to-face cohorts using multivariable regression analyses. ResultsA total of 2254 patients were included in the face-to-face IC cohort and 885 patients in the eIC cohort. Full consent was more often obtained in the eIC than in the face-to-face cohort (415/885, 46.9% vs 876/2254, 38.9%, respectively). Apart from lower mean hemoglobin in the full consent group of the eIC cohort (8.5 vs 8.8; P=.0021), the characteristics of the full consenting patients did not differ between the eIC and face-to-face IC cohorts. In the eIC cohort, only age differed between the full consent and the nonresponse group (median 60 vs 56; P=.0002, respectively), whereas in the face-to-face IC cohort, the full consent group seemed healthier (ie, higher hemoglobin, lower glycated hemoglobin [HbA1c], lower C-reactive protein levels) than the nonresponse group. ConclusionsMore patients provided full consent using an eIC. In addition, the study population remained broadly similar. The face-to-face IC approach seemed to result in a healthier study population (ie, full consenting patients) than the patients without IC, while in the eIC cohort, the characteristics between consent groups were comparable. Thus, an eIC may lead to a better representation of the target population, increasing the generalizability of results.