Predictors of augmented renal clearance based on iohexol plasma clearance in critically ill children.

BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.

Incidence of and indications for sperm donor restriction - analysis of patients continuing treatment: a retrospective single-centre study.

RESEARCH QUESTION: What are the incidence of and indications for sperm donor restriction due to suspected/confirmed disease risk, and the future treatment choices of patients using these sperm donors? DESIGN: This single-centre retrospective study involved donors who had restrictions on the use of their imported spermatozoa from January 2010 to December 2019, and current or previous recipients. Indications for sperm restriction and the characteristics of patients undergoing medically assisted reproduction (MAR) treatment with these specimens at the time of restriction were collected. Differential characteristics of women who decided on whether or not to contintue the procedure were assessed. Characteristics potentially leading to treatment continuation were identified. RESULTS: Of 1124 sperm donors identified, 200 (17.8%) were restricted, most commonly for multifactorial (27.5%) and autosomal recessive (17.5%) disorders. The spermatozoa had been used for 798 recipients, of whom 172, receiving spermatozoa from 100 donors, were informed about the restriction and constituted the 'decision cohort'. The specimens from the restricted donors were accepted by 71 (approximately 40%) patients, with 45 (approximately 63%) eventually using the restricted donor for their future MAR treatment. The odds of accepting the restricted spermatozoa decreased with increasing age (OR 0.857, 95% CI 0.800-0.918, P < 0.001) and the time between MAR treatment and the restriction date (OR 0.806, 95% CI 0.713-0.911, P < 0.001). CONCLUSION: Donor restriction due to suspected/confirmed disease risk is relatively frequent. This affected a relevant number of women (around 800), of whom 172 (approximately 20%) had to decide whether or not to use these donors further. Although donor screening is being performed thoroughly, there remain health risks for donor children. Realistic counselling of all stakeholders involved is necessary.

Supportive care needs and utilization of bladder cancer patients undergoing radical cystectomy: A longitudinal study.

OBJECTIVES: Investigating supportive care (SC) needs and utilization/willingness to use SC services from diagnosis to one year after radical cystectomy in bladder cancer (BC) patients. MATERIALS & METHODS: A longitudinal cohort study was conducted in 90 BC patients at Ghent/Leuven University Hospitals between April 2017 and December 2020. The Supportive Care Needs Survey-short form (SCNS-SF34) was used before radical cystectomy, one, three, six and 12 months after radical cystectomy. Additional questions assessed utilization/willingness to use SC services. Linear mixed models were performed. RESULTS: The majority of BC patients report at least one moderate or high SC need at diagnosis (82%), month 1 (84%), month 3 (86%), month 6 (64%), and month 12 (60%). Significant decreases over time were seen for all domains (p < 0.001), except for sexuality (p = 0.275). From baseline to month 1, physical needs first significantly increased (p = 0.001) after which they decreased. Psychological (e.g. fears about the future) and informational (e.g. information on how to get better) needs were most common at baseline whereas physical (e.g. lack of energy) and informational needs were more common in the early postoperative phases. The majority of patients (ranging from 81% (month 1) to 91% (month 12)) did not make use of SC services and the majority of the patients (ranging from 81% (month 1) to 88% (month 12)) did not wish to talk about their problems to someone. Those willing to talk to someone preferred their physician. CONCLUSIONS: A clear gap exists between the large proportion of SC needs experienced by BC patients undergoing radical cystectomy and the low use of SC services.

TNFi-induced sustained clinical remission in peripheral spondyloarthritis patients cannot be maintained with a step-down strategy based on methotrexate.

OBJECTIVES: Treatment with golimumab monotherapy in early peripheral SpA (pSpA) results in higher rates of clinical remission compared with treatment in more longstanding disease. When reaching remission, treat-to-target recommendations suggest tapering of treatment. We therefore explored whether addition of MTX would permit discontinuation of golimumab in patients with pSpA in sustained clinical remission. METHODS: After a 2-year extension phase with golimumab treatment, patients with pSpA reaching clinical remission in the CRESPA trial were offered a tapering strategy leading to discontinuation of golimumab and replacement by MTX monotherapy. Patients were prospectively followed to assess the rate of sustained biologic-free clinical remission. In case of relapse of arthritis, enthesitis or dactylitis under MTX monotherapy, golimumab was restarted. RESULTS: Of the original 60 pSpA patients, 25 entered the step-down strategy. Currently, only 4 patients (16%) are still in sustained remission under MTX monotherapy. In 21 patients (84%), golimumab was reinstalled because of relapse of disease activity (n = 19) or development of adverse events related to MTX (n = 2). Restarting golimumab treatment promptly restored clinical remission in all patients within 12 weeks. CONCLUSION: In patients with early pSpA achieving clinical remission after 2 years of golimumab treatment, step-down therapy to monotherapy with MTX led to high rates of clinical relapse. This underscores the overall weak efficacy of MTX in maintaining clinical remission in pSpA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01426815.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

How are OCD Patients and Family Members Dealing with the Waxing and Waning Pattern of the COVID-19 Pandemic? Results of a Longitudinal Observational Study.

The current study aimed to investigate the impact of the COVID-19 pandemic on the mental health of people with OCD and the degree of family accommodation (FA) by live-in family members across phases of the lockdown measures imposed by the Belgian government. Forty-nine OCD patients and 26 live-in family members participated in the study. We assessed OCD symptom severity and FA of the live-in family members, as well as depressive symptoms, anxiety and stress levels and COVID-19 related psychological distress of patients and family members at four different timepoints: one month after the start of the lockdown (T1), during the gradual relaxation (T2), between the two waves (T3) and during the second wave (T4). Results showed that although COVID-19 related stress increased and decreased in accordance with the waxing and waning pattern of the pandemic, OCD symptoms showed an initial slight increase followed by a decrease at T3 and again at T4. Changes in family members' accommodation of symptoms followed the same course as the OCD symptoms. Furthermore, OCD symptoms correlated with depressive symptoms, anxiety and stress levels and COVID-19 related distress at all timepoints. It is important to involve family members in the treatment of OCD even during a pandemic. Clinicians should also pay attention to symptoms of depression, anxiety and stress during OCD treatment. Further research is necessary to entangle the causal relationship between OCD symptoms, FA and symptoms of depression, anxiety and stress.

Patient- versus physician-reported outcomes in prostate cancer patients receiving hypofractionated radiotherapy within a randomized controlled trial.

PURPOSE: The risk of developing acute radiotherapy(RT)-induced side effects may increase with hypofractionated RT. To detect treatment-related side effects, patient-reported outcomes (PROs) might be more reliable than physician-reported outcomes. Therefore, we tried to evaluate the rate of agreement between urinary and gastrointestinal (GI) side effects and the prevalence of side effects reported by patients and by physicians. METHODS: Data from a randomized controlled trial (RCT) comparing two hypofractionated RT schedules were used. Urinary (nocturia, incontinence, frequency, dysuria, and urgency) and GI (obstruction, diarrhea, vomiting, nausea, bloating, hemorragia, and incontinence) symptoms measured by the EORTC QLQ-C30 and PR-25 were used for PROs. The same symptoms were scored by the physician using the Common Terminology Criteria Adverse Events v4.0. Outcomes were reported at baseline, end of treatment, month 1, and month 3. PROs and physician-reported outcomes were converted in two categories (0 = no symptoms; 1 = symptoms of any severity) and were correlated using the kappa (κ) correlation statistics. Values below 0.40 were considered low agreement. In addition, the prevalence of symptoms was calculated. RESULTS: Data from 160 patients were used. The mean value for Cohen's κ was 0.31 (ranging between 0.04 and 0.55) and 0.23 (ranging between 0.04 and 0.47) for urinary and GI symptoms, respectively. Except for three symptoms at baseline, all symptoms reported by patients were higher than those reported by physicians. CONCLUSION: There is low agreement between symptoms reported by patients and physicians, with high rates of underreporting by the physician.

Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial.

BACKGROUND: The benefit of early integration of palliative care into oncological care is suggested to be due to increased psychosocial support. In Belgium, psychosocial care is part of standard oncological care. The aim of this randomised controlled trial is to examine whether early and systematic integration of palliative care alongside standard psychosocial oncological care provides added benefit compared with usual care. METHODS: In this randomised controlled trial, eligible patients were 18 years or older, and had advanced cancer due to a solid tumour, an European Cooperative Oncology Group performance status of 0-2, an estimated life expectancy of 12 months, and were within the first 12 weeks of a new primary tumour or had a diagnosis of progression. Patients were randomly assigned (1:1), by block design using a computer-generated sequence, either to early and systematic integration of palliative care into oncological care, or standard oncological care alone in a setting where all patients are offered multidisciplinary oncology care by medical specialists, psychologists, social workers, dieticians, and specialist nurses. The primary endpoint was change in global health status/quality of life scale assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ C30) at 12 weeks. The McGill Quality of Life Questionnaire (MQOL), which includes the additional existential wellbeing dimension, was also used. Analysis was by intention to treat. This trial is ongoing, but closed for accrual, and is registered with ClinicalTrials.gov, number NCT01865396. FINDINGS: From April 29, 2013, to Feb 29, 2016, we screened 468 patients for eligibility, of whom 186 were enrolled and randomly assigned to the early and systematic palliative care group (92 patients) or the standard oncological care group (94). Compliance at 12 weeks was 71% (65 patients) in the intervention group versus 72% (68) in the control group. The overall quality of life score at 12 weeks, by the EORTC QLQ C30, was 54·39 (95% CI 49·23-59·56) in the standard oncological care group versus 61·98 (57·02-66·95) in the early and systematic palliative care group (difference 7·60 [95% CI 0·59-14·60]; p=0·03); and by the MQOL Single Item Scale, 5·94 (95% CI 5·50-6·39) in the standard oncological care group versus 7·05 (6·59-7·50) in the early and systematic palliative care group (difference 1·11 [95% CI 0·49-1·73]; p=0.0006). INTERPRETATION: The findings of this study show that a model of early and systematic integration of palliative care in oncological care increases the quality of life of patients with advanced cancer. Our findings also show that early and systematic integration of palliative care is more beneficial for patients with advanced cancer than palliative care consultations offered on demand, even when psychosocial support has already been offered. Through integration of care, oncologists and specialised palliative care teams should work together to enhance the quality of life of patients with advanced cancer. FUNDING: Research Foundation Flanders, Flemish Cancer Society (Kom Op Tegen Kanker).

Point-of-care CRP matters: normal CRP levels reduce immediate antibiotic prescribing for acutely ill children in primary care: a cluster randomized controlled trial.

OBJECTIVE: Antibiotics are prescribed too often in acutely ill children in primary care. We examined whether a Point-of-Care (POC) C-reactive Protein (CRP) test influences the family physicians' (FP) prescribing rate and adherence to the Evidence Based Medicine (EBM) practice guidelines. DESIGN: Cluster randomized controlled trial. SETTING: Primary care, Flanders, Belgium. INTERVENTION: Half of the children with non-severe acute infections (random allocation of practices to perform POC CRP or not) and all children at risk for serious infection were tested with POC CRP. SUBJECTS: Acutely ill children consulting their FP. MAIN OUTCOME MEASURE: Immediate antibiotic prescribing. RESULTS: 2844 infectious episodes recruited by 133 FPs between 15 February 2013 and 28 February 2014 were analyzed. A mixed logistic regression analysis was performed. Compared to episodes in which CRP was not tested, the mere performing of POC CRP reduced prescribing in case EBM practice guidelines advise to prescribe antibiotics (adjusted odds ratio (aOR) 0.54 (95% Confidence Interval (CI) 0.33-0.90). Normal CRP levels reduced antibiotic prescribing, regardless of whether the advice was to prescribe (aOR 0.24 (95%CI 0.11-0.50) or to withhold (aOR 0.31 (95%CI 0.17-0.57)). Elevated CRP levels did not increase antibiotic prescribing. CONCLUSION: Normal CRP levels discourage immediate antibiotic prescribing, even when EBM practice guidelines advise differently. Most likely, a normal CRP convinces FPs to withhold antibiotics when guidelines go against their own gut feeling. Future research should focus on whether POC CRP can effectively identify children that benefit from antibiotics more accurately, without increasing the risks of under-prescribing. Key points What is previously known or believed on this topic •Antibiotics are prescribed too often for non-severe conditions. Point-of-care (POC) C-reactive Protein (CRP) testing without guidance does not reduce immediate antibiotic prescribing in acutely ill children in primary care. What this research adds •FPs clearly consider CRP once available: normal CRP levels discourage immediate antibiotic prescribing, even when EBM practice guidelines advise differently. Most likely, a normal CRP convinces FPs to withhold antibiotics when guidelines go against their own gut feeling. •Future research should focus on whether POC CRP can effectively identify children that benefit from antibiotics more accurately, without increasing the risks of under-prescribing.

An Adjunctive Multi-family Group Intervention with or without Patient Participation during an Inpatient Treatment for Adolescents with an Eating Disorder: A Pilot Study.

This study reports on a pilot study of a family group intervention with or without patient participation adjunctive to a specialized inpatient treatment for eating disorders (EDs). Participants were 112 female adolescent ED inpatients and one or both of their parents. The parents were invited to participate in an adjunctive multi-family group with patient (MFT) or in a similar multi-parent group without patient participation (MPT). Questionnaires assessing ED symptoms, family functioning and caregiving experiences were administered before and after intervention. Post-intervention results obtained from both patient and parent(s) indicated that improvement in ED symptoms and parental burden occurred after both types of interventions. Family functioning improved differently according to the informant: fathers reported an improvement of general family functioning, patients reported an improvement of problem solving and mothers reported a decrease in problem solving across both formats. This study emphasized the importance of including a multi-informant approach in family interventions. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

The Development and Validation of the Patient Participation Culture Tool for Inpatient Psychiatric Wards (PaCT-PSY).

Patient participation is an important topic in mental health and receives increased attention along with deinstitutionalization. No tool exists to measure healthcare worker-related factors that influence patient participation. A three-staged study was conducted to develop and validate the 'Patient Participation Culture Tool for inpatient PSYchiatric wards' (PaCT-PSY), and to analyse its psychometric properties (n=603). The 60-items tool, comprising thirteen components, showed content validity, strong psychometric properties, and a high internal consistency. The PaCT-PSY measures the patient participation culture on psychiatric wards by exploring healthcare worker's factors influencing patient participation. It enables researchers, practitioners and administrators to develop tailored actions.

The effectiveness of an e-learning course on medication calculation in nursing students: a clustered quasi-experimental study.

AIM: To evaluate the effectiveness of an e-learning course compared with a face-to-face lecture on medication calculation. BACKGROUND: The current knowledge on medication calculation of nursing students and nurses is insufficient to provide safe care. DESIGN: A stratified-clustered quasi-experimental study. METHODS: A random selection of nursing schools were allocated to the e-learning course (intervention group) (seven schools; 189 students) or face-to-face lecture (control group) (six schools, 222 students). Students in both groups completed a validated medication calculation test (maximum score: 16) prior to the course (T0), immediately after the course (T1) and 3 months later (T2). A linear mixed model was used for data analysis. RESULTS: Medication calculation skills improved significantly more by the face-to-face lecture than e-learning course. Students in both groups significantly improved in medication calculation skills immediately after the course (T1) and 3 months later. The results flattened at T2 with a significant decline in the intervention group between T1 and T2 and a non-significant decline in the control group. Based on a subgroup analysis, improvement in medication calculation skills at T2 could only be observed in vocational-level (sub degree) nursing students receiving a face-to-face course. CONCLUSIONS: Both medication calculation courses had a positive effect on medication calculation skills. Students receiving traditional face-to-face lecture improved significantly more than the students receiving the e-learning course.

Role of angiogenic factors/cell adhesion markers in serum of cirrhotic patients with hepatopulmonary syndrome.

BACKGROUND & AIMS: Hepatopulmonary syndrome is a complication of chronic liver disease resulting in increased morbidity and mortality. It is caused by intrapulmonary vascular dilations and arteriovenous connections with devastating influence on gas exchange. The pathogenesis is not completely understood but evidence mounts for angiogenesis. Aims of this study were to identify angiogenic factors in serum of patients with hepatopulmonary syndrome and to study the possibility to predict its presence by these factors. METHODS: Multiplex assays were used to measure the concentration of angiogenic factors in patients with (n = 30) and without hepatopulmonary syndrome (n = 30). Diagnosis was based on the presence of gas exchange abnormality and intrapulmonary vasodilations according to published guidelines. RESULTS: Patients with and without hepatopulmonary syndrome had similar MELD scores (median: 11.2 vs. 11.6; P = 0.7), Child-Pugh score (P = 0.7) and PaCO2 values (median: 35 vs. 37; P = 0.06). PaO2 and P(A-a) O2 gradient were significantly different (respectively median of 80 vs. 86, P = 0.02; and 24 vs. 16, P = 0.004). Based on area under the curve (AUC) data and P-values, the best predictors were vascular cell adhesion molecule 1 (VCAM1) (AUC = 0.932; P < 0.001) and intercellular adhesion molecule 3 (ICAM3) (AUC = 0.741; P = 0.003). Combining these factors results in an AUC of 0.99 (after cross-validation still 0.99). CONCLUSIONS: VCAM1 and ICAM3 might be promising biomarkers for predicting hepatopulmonary syndrome. Combining these factors results in an AUC of 0.99 and a negative predictive value of 100%. Determining the concentration of these biomarkers might be a screening method to detect hepatopulmonary syndrome. The use of these biomarkers should be validated in larger groups of patients.

Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort.

INTRODUCTION: Bone marrow oedema (BMO) of the sacroiliac joints (SIJs) is a hallmark of axial spondyloarthritis (SpA). However, the relationship between the extent of BMO and disease phenotype is poorly understood. OBJECTIVE: To assess the link between BMO of the SIJs and gut inflammation. We have also evaluated the correlation between BMO and established disease activity parameters. METHODS: Sixty-eight patients with axial SpA from the Gent Inflammatory Arthritis and spoNdylitis cohorT underwent ileocolonoscopy and MRI of the SIJs. Histopathological analysis and SPondyloArthritis Research Consortium of Canada (SPARCC) scores were performed. RESULTS: A significant higher SPARCC score (median (range)) was observed in axial SpA patients showing chronic gut inflammation (16.9 (3.8-68.3)) compared with axial SpA patients showing normal gut histology (9.8 (0.0-45.0); p<0.05). In a multiple linear regression model, we identified, besides chronic gut inflammation (effect size of 11.3, 95% CI (2.1 to 20.4)), male sex (effect size of 10.5, 95% CI (3.3 to 17.8)) to be independently associated to the extent of BMO. There was a low to moderate correlation between the degree of BMO and C-reactive protein(r=0.39, p=0.002) and Ankylosing Spondylitis Disease Activity Score (r=0.35, p=0.007). CONCLUSIONS: Higher degrees of BMO were observed in patients showing chronic gut inflammation. These data solidify a link between mucosal inflammation and progressive disease in axial SpA.

RANKL blockade for erosive hand osteoarthritis: a randomized placebo-controlled phase 2a trial.

Erosive hand osteoarthritis (OA) is a prevalent and disabling disease with limited treatment options. Here we present the results of a monocentric, placebo-controlled, double-blind, randomized phase 2a clinical trial with denosumab, a receptor activator of nuclear factor-κB ligand inhibitor, evaluating the effects on structure modification in erosive hand OA. Patients were randomized to 48 weeks treatment with denosumab 60 mg every 3 months (n = 51, 41 females) or placebo (n = 49, 37 females). The primary (radiographic) endpoint was the change in the total Ghent University Scoring System (GUSS) at week 24, where positive changes correspond to remodeling and negative changes to erosive progression. Secondary endpoints were the change in the GUSS at week 48 and the number of new erosive joints at week 48 by the anatomical phase scoring system. Baseline mean GUSS (standard deviation) of target joints was 155.9 (69.3) in the denosumab group and 158.7 (46.8) in the placebo group. The primary endpoint was met with an estimated difference between groups of 8.9 (95% confidence interval (CI) 1.0 to 16.9; P = 0.024) at week 24. This effect was confirmed at week 48 (baseline adjusted GUSS (standard error of the mean) denosumab and placebo were 163.5 (2.9) and 149.2 (3.9), respectively; with an estimated difference between groups of 14.3 (95% CI 4.6 to 24.0; P = 0.003)). At patient level, more new erosive joints were developed in the placebo group compared with denosumab at week 48 (odds ratio 0.24 (95% CI 0.08 to 0.72); P = 0.009). More adverse events occurred in the placebo group (125 events in 44 patients (90%)) compared with the denosumab group (97 events in 41 patients (80%)). These results demonstrate that denosumab has structure modifying effects in erosive hand OA by inducing remodeling and preventing new erosive joints. EU Clinical Trials Register identifier 2015-003223-53 .

Impact of model-informed precision dosing in adults receiving vancomycin via continuous infusion: a randomized, controlled clinical trial.

BACKGROUND: Vancomycin is a commonly prescribed antibiotic to treat gram-positive infections. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. However, in most countries, steady-state plasma concentrations are used as a surrogate parameter of target AUC/MIC, but this practice has some drawbacks. Hence, direct AUC-guided monitoring of vancomycin using model-informed precision dosing (MIPD) tools has been proposed for earlier attainment of target concentrations and reducing vancomycin-related nephrotoxicity. However, solid scientific evidence for these benefits in clinical practice is still lacking. This randomized controlled trial (RCT) aims to investigate the clinical utility of MIPD dosing of vancomycin administered via continuous infusion in hospitalized adults. METHODS: Participants from 11 wards at two Belgian hospitals are randomly allocated to the intervention group or the standard-of-care comparator group. In the intervention group, clinical pharmacists perform dose calculations using CE-labeled MIPD software and target an AUC24h of 400 to 600 mg × h/L, whereas patients in the comparator group receive standard-of-care dosing and monitoring according to the institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400-600 between 48 and 72 h after start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury (AKI) during and until 48 h after stop of vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400-600 between 72 and 96 h after start of vancomycin treatment, and the proportion of time within the target AUC24h/MIC of 400-600. DISCUSSION: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment. TRIAL REGISTRATION: EudraCT number: 2021-003670-31. Registered June 28, 2021. CLINICALTRIALS: gov identifier: NCT05535075. Registered September 10, 2022. Protocol version 3, protocol date: April 21, 2023.

Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model.

OBJECTIVE: To assess the rates and explore predictors of microscopic gut inflammation in a cohort of patients with axial and peripheral spondyloarthritis (SpA). METHODS: Ileocolonoscopy was performed in 65 patients with axial and peripheral SpA from the Gent Inflammatory Arthritis and spoNdylitis cohorT. Histopathological analysis and scoring were performed by an experienced pathologist. RESULTS: Overall, 46.2% of the patients with SpA showed microscopic gut inflammation. In axial SpA, the following parameters were independently associated with gut involvement: male sex (OR=8.9, p=0.035); high disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (OR=2.05, p=0.032); restricted spinal mobility measured by the Bath Ankylosing Spondylitis Metrology Index (OR=1.94, p=0.009); and younger age (OR=0.85, p=0.013). No clear association was found for human leucocyte antigen-B27 status, presence of peripheral arthritis, enthesitis, uveitis, psoriasis, intake of non-steroidal anti-inflammatory drugs and family history of SpA. The prevalence of gut inflammation in non-radiographic axial SpA and ankylosing spondylitis was comparable. CONCLUSIONS: The prevalence of microscopic gut inflammation in SpA remains unaltered over time. Younger age (shorter symptom duration), progressive disease, male sex and higher disease activity are independently associated with microscopic gut inflammation in axial SpA.

Microdialysis as a safe and feasible method to study target-site piperacillin-tazobactam disposition in septic piglets and children.

OBJECTIVES: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project. METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability. RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children. CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.

A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19.

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.