Estimating uncertainty when providing individual cardiovascular risk predictions: A Bayesian survival analysis.

BACKGROUND: Cardiovascular disease (CVD) risk scores provide point estimates of individual risk without uncertainty quantification. The objective of the current study was to demonstrate the feasibility and clinical utility of calculating uncertainty surrounding individual CVD-risk predictions using Bayesian methods. METHODS AND RESULTS: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), a Bayesian Weibull model was derived to predict the 10-year risk of recurrent CVD events. Model coefficients and individual predictions were very similar to that of a traditional ('frequentist') model but the Bayesian model also predicted 95% credible intervals (CIs) surrounding individual risk estimates. The median width of the individual 95%CrI was 5.3% (IQR 3.6-6.5) and 17% of the population had a 95%CrI width of 10% or greater. The uncertainty decreased with increasing sample size used for derivation of the model. Combining the Bayesian Weibull model with sampled hazard ratios based on trial reports may be used to estimate individual absolute risk reduction with uncertainty measures and the probability that a treatment option will result in a clinically relevant risk reduction. INTERPRETATION: Estimating uncertainty surrounding individual CVD risk predictions using Bayesian methods is feasible. The uncertainty regarding individual risk predictions could have several applications in clinical practice, like the comparison of different treatment options or by calculating the probability of the individual risk being below a certain treatment threshold. However, as the individual uncertainty measures only reflect sampling error and no biases in risk prediction, physicians should be familiar with the interpretation before widespread clinical adaption.

Does high hepatic bioavailability enhance the effect of oral compared to subcutaneous glucocorticoids?

OBJECTIVES: Glucocorticoids (GC) are important in the treatment of autoinflammatory disorders. Oral prednisolone ≤5 mg/day can be effective, but such doses are at or even below physiological daily endogenous GC production. We hypothesised that their immunosuppressive effect might be explained by high hepatic bioavailability of oral GC, exposing the liver to supraphysiological GC via the portal circulation. We tested this by comparing the effect of oral versus subcutaneous low-dose prednisolone, on erythrocyte sedimentation rate (ESR). METHODS: Patients with rheumatoid arthritis or psoriatic arthritis, elevated ESR (≥30 mm/h) and no current or recent GC therapy were eligible. In a pilot study (n=5), 5 mg/day oral prednisolone decreased ESR significantly, suggesting a sample size of 10 patients for a randomised, non-blinded crossover trial. Patients received 5 mg/day prednisolone for 2 periods of 4 days: one treatment period orally and one subcutaneously with a 10-day washout period between treatments. ESR was measured before (day 1 and 15) and after (day 5 and 19) each treatment course. RESULTS: 10 patients were included. ESR decreased after both oral and subcutaneous prednisolone, by -5.6 (20.9) and -5.8 (3.0) mm/h, respectively (p=0.98). The treatment order had no effect on the outcome. CONCLUSIONS: . Short-term oral low-dose GC therapy is not more effective than parental GC in decreasing ESR, arguing against therapeutic high hepatic bioavailability effects. More likely, systemic concentration peaks following administration explain why oral physiological steroid doses are clinically effective.

[Estimating glomerular filtration rate]. / Het schatten van de glomerulaire filtratiesnelheid.

Almost all laboratories in The Netherlands report an estimated glomerular filtration rate (eGFR) whenever a value for plasma creatinine is requested. This formula is based on gender and age, besides the plasma creatinine concentration, and sometimes also a correction for race is applied. While this GFR reporting improved the recognition of chronic kidney disease, the formulas used have intrinsic limitations. Moreover, recently a novel formula that obviates the need for a correction factor for race has been proposed. In this article the strengths and weaknesses of plasma creatinine and formulas based on that are discussed, following ten frequently asked questions.

Impact of the 2021 European Society for Cardiology prevention guideline's stepwise approach for cardiovascular risk factor treatment in patients with established atherosclerotic cardiovascular disease.

AIMS: This study aimed to evaluate the stepwise approach for cardiovascular (CV) risk factor treatment as outlined by the European Society for Cardiology 2021 guidelines on CV disease (CVD) prevention in patients with established atherosclerotic CVD (ASCVD). METHODS AND RESULTS: In patients with ASCVD, included in UCC-SMART (n = 8730) and European parts of the REACH registry (n = 18 364), the 10-year CV risk was estimated using SMART2. Treatment effects were derived from meta-analyses and trials. Step 1 recommendations were LDL cholesterol (LDLc) < 1.8 mmol/L, systolic blood pressure (SBP) < 140 mmHg, using any antithrombotic medication, sodium-glucose co-transporter 2 (SGLT2) inhibition, and smoking cessation. Step 2 recommendations were LDLc < 1.4 mmol/L, SBP < 130 mmHg, dual-pathway inhibition (DPI, aspirin plus low-dose rivaroxaban), colchicine, glucagon-like peptide (GLP)-1 receptor agonists, and eicosapentaenoic acid. Step 2 was modelled accounting for Step 1 non-attainment. With current treatment, residual CV risk was 22%, 32%, and 60% in the low, moderate, and pooled (very) high European risk regions, respectively. Step 2 could prevent up to 198, 223 and 245 events per 1000 patients treated, respectively. Intensified LDLc reduction, colchicine, and DPI could be applied to most patients, preventing up to 57, 74, and 59 events per 1000 patients treated, respectively. Following Step 2, the number of patients with a CV risk of <10% could increase from 20%, 6.4%, and 0.5%, following Step 1, to 63%, 48%, and 12%, in the respective risk regions. CONCLUSION: With current treatment, residual CV risk in patients with ASCVD remains high across all European risk regions. The intensified Step 2 treatment options result in marked further reduction of residual CV risk in patients with established ASCVD. KEY FINDINGS: Guideline-recommended intensive treatment of patients with cardiovascular disease could prevent additional 198-245 new cardiovascular events for every 1000 patients treated.

Patients with established cardiovascular disease are at high risk for new cardiovascular events. The European Society of Cardiology guideline for the prevention of cardiovascular disease introduced a stepwise treatment approach. Step 1 in this approach are treatments that apply to all patients, and Step 2 are intensive treatments that can be prescribed to patients who are still at high risk of new events even with Step 1 treatments. The current study investigates the effect of Steps 1 and 2 on the risk of cardiovascular disease in 27 094 patients all across Europe. With the conventional treatments of Step 1 the risk of cardiovascular disease remains high, with a 10-year risk of new events higher than 10% in 80­99% of patients. The intensive treatment options from Step 2 could prevent additional 198­245 new cardiovascular events for every 1000 patients that are treated. With intensive treatment, up to 63% of patients could achieve a 10-year risk of new cardiovascular disease below 10%.

[Milk-alkali syndrome: a careful history is crucial in diagnosing hypercalcemia]. / Melk-alkalisyndroom.

BACKGROUND: Milk-alkali syndrome is a rare cause of hypercalcemia in the Netherlands, due to ingestion of large amounts of calcium and absorbable alkali. CASE DESCRIPTION: A 38-year-old female patient was admitted with severe stomach pain, vomiting and weight loss. Laboratory results showed hypercalcemia and acute kidney injury. We initially suspected that the hypercalcemia was related to primary hyperparathyroidism, a malignancy with bone metastasis or a granulomatous disease. Gastroduodenoscopy, however, revealed a duodenal ulcer, which turned out to be Helicobacter pylori-related. A thorough history revealed that the patient had consumed large amounts of milk and antacids to relieve symptoms of heartburn. In light of this history, milk-alkali syndrome was diagnosed. CONCLUSION: The case aims to underline the importance of a thorough history in patients with hypercalcemia. The use of over-the-counter medications and dairy products should be evaluated in all patients presenting with hypercalcemia.

Why not to pick your nose: Association between nose picking and SARS-CoV-2 incidence, a cohort study in hospital health care workers.

BACKGROUND: Hospital health care workers (HCW) are at increased risk of contracting SARS-CoV-2. We investigated whether certain behavioral and physical features, e.g. nose picking and wearing glasses, are associated with infection risk. AIM: To assess the association between nose picking and related behavioral or physical features (nail biting, wearing glasses, and having a beard) and the incidence of SARS-CoV-2-infection. METHODS: In a cohort study among 404 HCW in two university medical centers in the Netherlands, SARS-CoV-2-specific antibodies were prospectively measured during the first phase of the pandemic. For this study HCW received an additional retrospective survey regarding behavioral (e.g. nose picking) and physical features. RESULTS: In total 219 HCW completed the survey (response rate 52%), and 34/219 (15.5%) became SARS-CoV-2 seropositive during follow-up from March 2020 till October 2020. The majority of HCW (185/219, 84.5%) reported picking their nose at least incidentally, with frequency varying between monthly, weekly and daily. SARS-CoV-2 incidence was higher in nose picking HCW compared to participants who refrained from nose picking (32/185: 17.3% vs. 2/34: 5.9%, OR 3.80, 95% CI 1.05 to 24.52), adjusted for exposure to COVID-19. No association was observed between nail biting, wearing glasses, or having a beard, and the incidence of SARS-CoV-2 infection. CONCLUSION: Nose picking among HCW is associated with an increased risk of contracting a SARS-CoV-2 infection. We therefore recommend health care facilities to create more awareness, e.g. by educational sessions or implementing recommendations against nose picking in infection prevention guidelines.

Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

The efficacy of aspirin to inhibit platelet aggregation in patients hospitalised with a severe infection: a multicentre, open-label, randomised controlled trial.

Patients with severe infection have an increased risk of cardiovascular events. A possible underlying mechanism is inflammation-induced platelet aggregation. We investigated whether hyperaggregation occurs during infection, and whether aspirin inhibits this. In this multicentre, open-label, randomised controlled trial, patients hospitalised due to acute infection were randomised to receive 10 days of aspirin treatment (80 mg 1dd or 40 mg 2dd) or no intervention (1:1:1 allocation). Measurements were performed during infection (T1; days 1-3), after intervention (T2; day 14) and without infection (T3; day > 90). The primary endpoint was platelet aggregation measured by the Platelet Function Analyzer® closure time (CT), and the secondary outcomes were serum and plasma thromboxane B2 (sTxB2 and pTxB2). Fifty-four patients (28 females) were included between January 2018 and December 2020. CT was 18% (95%CI 6;32) higher at T3 compared with T1 in the control group (n = 16), whereas sTxB2 and pTxB2 did not differ. Aspirin prolonged CT with 100% (95%CI 77; 127) from T1 to T2 in the intervention group (n = 38), while it increased with only 12% (95%CI 1;25) in controls. sTxB2 decreased with 95% (95%CI - 97; - 92) from T1 to T2, while it increased in the control group. pTxB2 was not affected compared with controls. Platelet aggregation is increased during severe infection, and this can be inhibited by aspirin. Optimisation of the treatment regimen may further diminish the persisting pTxB2 levels that point towards remaining platelet activity. This trial was registered on 13 April 2017 at EudraCT (2016-004303-32).

Effect of anti-inflammatory therapy on vascular biomarkers for subclinical cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: To assess the effect of 4 years of anti-inflammatory therapy on markers of subclinical vascular disease in rheumatoid arthritis patients. METHODS: Carotid intima media thickness (IMT), augmentation index (AIx@75) and pulse wave velocity (PWV) measurements were performed repeatedly in 61 RA patients (30 early RA starting with csDMARDs and 31 established RA starting with adalimumab) for 4 years. These markers were also measured in 29 controls with osteoarthritis at baseline (BL). RESULTS: IMT and AIx@75 at BL were higher in RA compared to OA, while PWV was higher in OA. In RA patients, AIx@75 and PWV decreased in the first 6 months after starting anti-inflammatory therapy. At 48 M, the level of AIx@75 remained lower than before therapy, while PWV at 48 M was comparable to BL (AIx@75: BL 28% (95% confidence interval 25-30%), 6 M 23% (20-26%), 48 M 25% (22-28%); PWV: BL 8.5 (7.8-9.2), 6 M 8.0 (7.1-8.9), 48 M 8.6 (7.6-9.6) m/s). IMT remained stable. There was an effect of disease activity (longitudinally, adjusted for changes over time) on IMT, AIx@75 and PWV. CONCLUSION: This study suggests modest beneficial changes in some surrogate markers of subclinical vascular disease after anti-inflammatory therapy. These changes were associated with improvement in disease activity markers. Whether or not these beneficial changes ultimately predict a reduction in clinicalcardiovascular endpoints remains to be established in prospective studies.

[A man with a low voice]. / Een man met een zware stem.

A 57-year old man with several non-specific complaints is found to have severe hypothyroidism. Only then he realizes that his voice may have changed. A recording of his voice during and after full recovery illustrates the profound effects that vocal cord myxedema may have of a patient's voice.

[Are guidelines still supportive in clinical practice?] / Zijn richtlijnen nog ondersteunend in de praktijk?

Clinical practice guidelines are fundamental to support knowledge and decision making of healthcare professionals in many disciplines. They can contribute to reducing undesirable practice variation, educating patients, and monitoring care. However, the burden increases if the number and size of guidelines continues to increase and as more side effects occur due to injudicious use, both in the professional and policy setting. Restricting the scope and finding the right balance between completeness and conciseness are major challenges for guideline developers and stakeholders. Ongoing innovation projects are working on improving accessibility, updating, and applicability in multimorbidity through optimal use of digital technologies. As long as healthcare professionals are in the lead in guideline development and involved in policy making, doctors can continue to rely on guidelines, if used correctly for the right care.

[A man with cola-coloured urine]. / Een man met colakleurige urine.

A 37-year-old man was referred to the Emergency Department of the FundashonMariadal hospital in Bonaire because of an abnormal color of urine after having exercised heavily. Laboratory tests showed rhabdomyolysis with a creatine kinase level of 112.114 U/L. After hyperhydration creatine kinase values decreased rapidly, renal function remained normal.

Recent infection with HCoV-OC43 may be associated with protection against SARS-CoV-2 infection.

Antibodies against seasonal human coronaviruses (HCoVs) are known to cross-react with SARS-CoV-2, but data on cross-protective effects of prior HCoV infections are conflicting. In a prospective cohort of healthcare workers (HCWs), we studied the association between seasonal HCoV (OC43, HKU1, 229E and NL63) nucleocapsid protein IgG and SARS-CoV-2 infection during the first pandemic wave in the Netherlands (March 2020 - June 2020), by 4-weekly serum sampling. HCW with HCoV-OC43 antibody levels in the highest quartile, were less likely to become SARS-CoV-2 seropositive when compared with those with lower levels (6/32, 18.8%, versus 42/97, 43.3%, respectively: p = 0.019; HR 0.37, 95% CI 0.16-0.88). We found no significant association with HCoV-OC43 spike protein IgG, or with antibodies against other HCoVs. Our results indicate that the high levels of HCoV-OC43-nucleocapsid antibodies, as an indicator of a recent infection, are associated with protection against SARS-CoV-2 infection; this supports and informs efforts to develop pancoronavirus vaccines.

[New predictions in prevention guidelines: improved estimation of cardiovascular risks]. / Nieuwe voorspellingen in preventieve richtlijnen.

Estimation of 10-year cardiovascular risk has a central role in Cardiovascular Prevention Guidelines in order to identify people at high risk that would benefit from lifestyle modification and risk factor treatment. In the recently issued European Guidelines age-dependent 10-year risk thresholds have been introduced, as well as lifetime risk estimation and estimation of treatment benefit, which all can be used in clinical practice to further individualize treatment of cardiovascular risk factors. Also cardiovascular risk prediction in people with diabetes and patients with already established cardiovascular disease are now available to estimate residual cardiovascular risk after initial lifestyle and risk factor treatment to guide individual intensification of risk factor treatment to further reduce the risk of a first or subsequent cardiovascular event.

The Prognostic Accuracy of Clinical Judgment Versus a Validated Frailty Screening Instrument in Older Patients at the Emergency Department: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: To compare the prognostic accuracy of clinical judgment for frailty in older patients at the emergency department with a validated screening instrument and patient-perceived frailty. METHODS: A prospective cohort study in patients 70 years of age and older in 2 Dutch EDs with a follow-up of 3 months. A dichotomous question was asked to the physician and patient: "Do you consider the patient / yourself to be frail?" The Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) was used as a validated screening instrument. The primary composite outcome consisted of either functional decline, institutionalization, or mortality. RESULTS: A total of 736 patients were included. The physician identified 59% as frail, compared with 49% by ISAR-HP and 43% by patients themselves. The level of agreement was fair (Fleiss Kappa, 0.31). After 3 months, 31% of the patients experienced at least 1 adverse health outcome. The sensitivity was 79% for the physician, 72% for ISAR-HP, 61% for the patient, and 48% for all 3 combined. The specificity was 50% for the physician, 63% for ISAR-HP, 66% for the patient, and 85% for all 3 positive. The highest positive likelihood ratio was 3.03 (physician, ISAR-HP, patient combined), and the lowest negative likelihood ratio was 0.42 (physician). The areas under the receiver operating curves were all poor: 0.68 at best for ISAR-HP. CONCLUSION: Clinical judgment for frailty showed fair agreement with a validated screening instrument and patient-perceived frailty. All 3 instruments have poor prognostic accuracy, which does not improve when combined. These findings illustrate the limited prognostic value of clinical judgment as a frailty screener in older patients at the ED.