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.

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.

[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.

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.

Time since SARS-CoV-2 infection and humoral immune response following BNT162b2 mRNA vaccination.

BACKGROUND: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. METHODS: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n = 18, median two months, IQR 2-3), with infection-vaccination interval over six months (n = 19, median nine months, IQR 9-10), and to those not previously infected (n = 73). FINDINGS: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2.5 fold (p = 0.003) and 3.4 fold (p < 0.001) for binding antibody levels, and 6.4 and 7.2 fold for neutralisation titres, respectively (both p < 0.001). The second vaccine dose yielded no further substantial improvement of the humoral response in the previously infected participants (0.97 fold, p = 0.92), while it was associated with a 4 fold increase in antibody binding levels and 18 fold increase in neutralisation titres in previously uninfected participants (both p < 0.001). Adjustment for potential confounding of sex and age did not affect these findings. INTERPRETATION: Delaying the second vaccination in individuals infected up to ten months prior may constitute a more efficient use of limited vaccine supplies. FUNDING: Netherlands Organization for Health Research and Development ZonMw; Corona Research Fund Amsterdam UMC; Bill & Melinda Gates Foundation.

Communicating personalised statin therapy-effects as 10-year CVD-risk or CVD-free life-expectancy: does it improve decisional conflict? Three-armed, blinded, randomised controlled trial.

OBJECTIVE: To determine whether communicating personalised statin therapy-effects obtained by prognostic algorithm leads to lower decisional conflict associated with statin use in patients with stable cardiovascular disease (CVD) compared with standard (non-personalised) therapy-effects. DESIGN: Hypothesis-blinded, three-armed randomised controlled trial SETTING AND PARTICIPANTS: 303 statin users with stable CVD enrolled in a cohort INTERVENTION: Participants were randomised in a 1:1:1 ratio to standard practice (control-group) or one of two intervention arms. Intervention arms received standard practice plus (1) a personalised health profile, (2) educational videos and (3) a structured telephone consultation. Intervention arms received personalised estimates of prognostic changes associated with both discontinuation of current statin and intensification to the most potent statin type and dose (ie, atorvastatin 80 mg). Intervention arms differed in how these changes were expressed: either change in individual 10-year absolute CVD risk (iAR-group) or CVD-free life-expectancy (iLE-group) calculated with the SMART-REACH model (http://U-Prevent.com). OUTCOME: Primary outcome was patient decisional conflict score (DCS) after 1 month. The score varies from 0 (no conflict) to 100 (high conflict). Secondary outcomes were collected at 1 or 6 months: DCS, quality of life, illness perception, patient activation, patient perception of statin efficacy and shared decision-making, self-reported statin adherence, understanding of statin-therapy, post-randomisation low-density lipoprotein cholesterol level and physician opinion of the intervention. Outcomes are reported as median (25th- 75th percentile). RESULTS: Decisional conflict differed between the intervention arms: median control 27 (20-43), iAR-group 22 (11-30; p-value vs control 0.001) and iLE-group 25 (10-31; p-value vs control 0.021). No differences in secondary outcomes were observed. CONCLUSION: In patients with clinically manifest CVD, providing personalised estimations of treatment-effects resulted in a small but significant decrease in decisional conflict after 1 month. The results support the use of personalised predictions for supporting decision-making. TRIAL REGISTRATION: NTR6227/NL6080.

Serologic Surveillance and Phylogenetic Analysis of SARS-CoV-2 Infection Among Hospital Health Care Workers.

Importance: It is unclear when, where, and by whom health care workers (HCWs) working in hospitals are infected with SARS-CoV-2. Objective: To determine how often and in what manner nosocomial SARS-CoV-2 infection occurs in HCW groups with varying exposure to patients with COVID-19. Design, Setting, and Participants: This cohort study comprised 4 weekly measurements of SARS-CoV-2-specific antibodies and collection of questionnaires from March 23 to June 25, 2020, combined with phylogenetic and epidemiologic transmission analyses at 2 university hospitals in the Netherlands. Included individuals were HCWs working in patient care for those with COVID-19, HCWs working in patient care for those without COVID-19, and HCWs not working in patient care. Data were analyzed from August through December 2020. Exposures: Varying work-related exposure to patients infected with SARS-CoV-2. Main Outcomes and Measures: The cumulative incidence of and time to SARS-CoV-2 infection, defined as the presence of SARS-CoV-2-specific antibodies in blood samples, were measured. Results: Among 801 HCWs, there were 439 HCWs working in patient care for those with COVID-19, 164 HCWs working in patient care for those without COVID-19, and 198 HCWs not working in patient care. There were 580 (72.4%) women, and the median (interquartile range) age was 36 (29-50) years. The incidence of SARS-CoV-2 was increased among HCWs working in patient care for those with COVID-19 (54 HCWs [13.2%; 95% CI, 9.9%-16.4%]) compared with HCWs working in patient care for those without COVID-19 (11 HCWs [6.7%; 95% CI, 2.8%-10.5%]; hazard ratio [HR], 2.25; 95% CI, 1.17-4.30) and HCWs not working in patient care (7 HCWs [3.6%; 95% CI, 0.9%-6.1%]; HR, 3.92; 95% CI, 1.79-8.62). Among HCWs caring for patients with COVID-19, SARS-CoV-2 cumulative incidence was increased among HCWs working on COVID-19 wards (32 of 134 HCWs [25.7%; 95% CI, 17.6%-33.1%]) compared with HCWs working on intensive care units (13 of 186 HCWs [7.1%; 95% CI, 3.3%-10.7%]; HR, 3.64; 95% CI, 1.91-6.94), and HCWs working in emergency departments (7 of 102 HCWs [8.0%; 95% CI, 2.5%-13.1%]; HR, 3.29; 95% CI, 1.52-7.14). Epidemiologic data combined with phylogenetic analyses on COVID-19 wards identified 3 potential HCW-to-HCW transmission clusters. No patient-to-HCW transmission clusters could be identified in transmission analyses. Conclusions and Relevance: This study found that HCWs working on COVID-19 wards were at increased risk for nosocomial SARS-CoV-2 infection with an important role for HCW-to-HCW transmission. These findings suggest that infection among HCWs deserves more consideration in infection prevention practice.

The Accuracy of Four Frequently Used Frailty Instruments for the Prediction of Adverse Health Outcomes Among Older Adults at Two Dutch Emergency Departments: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: Older adults presenting to the emergency department (ED) are at high risk of adverse health outcomes. This study aimed to evaluate the accuracy of 4 frequently used screening instruments for the prediction of adverse health outcomes among older adults in the ED. METHODS: This was a prospective cohort study in patients ≥70 years of age presenting to the ED in 2 hospitals in the Netherlands. Screening instruments included the acutely presenting older patient screening program (APOP) (providing 2 risk scores-functional decline [APOP1] and mortality [APOP2]), the International Resident Assessment Instrument Emergendy Department screener (InterRAI ED), the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP), and the safety management system (VMS). The primary outcome measure was a composite outcome encompassing functional decline, institutionalization, and mortality at 3 months after ED presentation. Other follow-up time points were 1 and 6 months. Analyses were performed to assess prognostic accuracy. RESULTS: In total, 889 patients were included. After 3 months, 267 (31%) patients experienced at least 1 adverse outcome. The positive likelihood ratio ranged from 1.67 (VMS) to 3.33 (APOP1), and the negative likelihood ratio ranged from 0.41 (ISAR-HP) to 0.88 (APOP2). Sensitivity ranged from 17% (APOP2) to 74% (ISAR-HP), and specificity ranged from 63% (ISAR-HP) to 94% (APOP2). The area under the curve ranged from 0.62 (APOP2) to 0.72 (APOP1 and ISAR-HP). Calibration was reasonable for APOP1 and VMS. The prognostic accuracy was comparable across all outcomes and at all follow-up time points. CONCLUSION: The frailty screening instruments assessed in this study showed poor to moderate prognostic accuracy, which brings into question their usability in the prediction of adverse health outcomes among older adults who present to the ED.

Relationship between classic vascular risk factors and cumulative recurrent cardiovascular event burden in patients with clinically manifest vascular disease: results from the UCC-SMART prospective cohort study.

OBJECTIVE: The aim of the current study was to assess the relationship between classic cardiovascular risk factors and risk of not only the first recurrent atherosclerotic cardiovascular event, but also the total number of non-fatal and fatal cardiovascular events in patients with recently clinically manifest cardiovascular disease (CVD). DESIGN: Prospective cohort study. SETTING: Tertiary care centre. PARTICIPANTS: 7239 patients with a recent first manifestation of CVD from the prospective UCC-SMART (Utrecht Cardiovascular Cohort - Second Manifestations of ARTerial disease) cohort study. OUTCOME MEASURES: Total cardiovascular events, including myocardial infarction, stroke, vascular interventions, major limb events and cardiovascular mortality. RESULTS: During a median follow-up of 8.9 years, 1412 patients had one recurrent cardiovascular event, while 1290 patients had two or more recurrent events, with a total of 5457 cardiovascular events during follow-up. The HRs for the first recurrent event and cumulative event burden using Prentice-Williams-Peterson models, respectively, were 1.36 (95% CI 1.25 to 1.48) and 1.26 (95% CI 1.17 to 1.35) for smoking, 1.14 (95% CI 1.11 to 1.18) and 1.09 (95% CI 1.06 to 1.12) for non-high-density lipoprotein (HDL) cholesterol, and 1.05 (95% CI 1.03 to 1.07) and 1.04 (95% CI 1.03 to 1.06) for systolic blood pressure per 10 mm Hg. CONCLUSIONS: In a cohort of patients with established CVD, systolic blood pressure, non-HDL cholesterol and current smoking are important risk factors for not only the first, but also subsequent recurrent events during follow-up. Recurrent event analysis captures the full cumulative burden of CVD in patients.