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.

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.

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.

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.

Progressive Increase in Sacroiliac Joint and Spinal Lesions Detected on Magnetic Resonance Imaging in Healthy Individuals in Relation to Age.

OBJECTIVE: Magnetic resonance imaging (MRI) plays a pivotal role in spondyloarthritis (SpA) diagnosis. However, a detailed description of MRI findings of the sacroiliac (SI) joints and spine in healthy individuals is currently lacking. This study was undertaken to evaluate the occurrence of MRI-detected SI joint and spinal lesions in healthy individuals in relation to age. METHODS: Ninety-five healthy subjects (ages 20-49 years) underwent MRI of the SI joints and spine. Bone marrow edema (BME) and structural lesions of the SI joints were scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Spinal inflammatory and structural lesions were evaluated using the SPARCC MRI spine inflammation index and the Canada-Denmark MRI scoring system, respectively. Fulfillment of the Assessment of SpondyloArthritis international Society definition of a positive MRI for sacroiliitis/spondylitis was reviewed. Findings were compared to MRIs of axial SpA patients from the Belgian Inflammatory Arthritis and Spondylitis cohort. RESULTS: Of the subjects ≥30 years old, 17.2% fulfilled the definition of a positive MRI for sacroiliitis, but this occurred rarely in younger subjects. SI joint erosions (20.0%) and fat metaplasia (13.7%) were detected across all age groups. Erosions were more frequently visualized in subjects ages ≥40 years (39.3%). Spinal BME (35.7%) and fat metaplasia (28.6%) were common in subjects older than 40 years. Nonetheless, only 1 subject had ≥3 corner inflammatory lesions. SI joint and spinal SPARCC scores and total structural lesions scores increased progressively with age. CONCLUSION: Contrary to what is commonly believed, structural MRI-detected SI joint lesions are frequently seen in healthy individuals. Especially in older subjects, the high occurrence of inflammatory and structural MRI-detected lesions impacts their specificity for SpA, which has important implications for the interpretation of MRIs in patients with a clinical suspicion of SpA.

Mental Health and Quality of Life among Patients with Cancer during the SARS-CoV-2 Pandemic: Results from the Longitudinal ONCOVID Survey Study.

PURPOSE: This longitudinal survey study aimed to investigate the self-reported outcome measures of COVID-19 peritraumatic distress, depression, anxiety, stress, quality of life (QOL), and their associated factors in a cohort of cancer patients treated at a tertiary care hospital during the SARS-CoV-2 pandemic. METHODS: Surveys were administered at four time points between 1 April 2020 and 18 September 2020. The surveys included the CPDI, DASS-21, and WHOQOL-BREF questionnaires. RESULTS: Survey response rates were high (61.0% to 79.1%). Among the 355 participants, 71.3% were female, and the median age was 62.2 years (IQR, 53.9 to 69.1). The majority (78.6%) were treated with palliative intention. An important proportion of the participants reported symptoms of COVID-19 peritraumatic distress (34.2% to 39.6%), depression (27.6% to 33.5%), anxiety (24.9% to 32.7%), and stress (11.4% to 15.7%) at any time point during the study period. We did not find clinically meaningful mental health and QOL differences during the study period, with remarkably little change in between the pandemic's first and second wave. We found no consistent correlates of mental health or QOL scores, including cancer type, therapy intention, and sociodemographic information. CONCLUSION: This cohort of cancer patients showed considerable resilience against mental health and QOL deterioration during the SARS-CoV-2 pandemic.

Nocturnal bladder emptying and Quality of Life in patients with spinal cord injury.

BACKGROUND: Little is known about the relationship between sleep disruption due to nocturnal bladder emptying and Quality of Life in patients with spinal cord injury. AIM: The aim of this study was to evaluate the possible influence of number of nocturnal bladder emptying, bladder emptying method and nocturnal incontinence on the Quality of Life of patients with spinal cord injury. DESIGN: The design of this paper is a cross-sectional descriptive study. SETTING: The setting is in- and outpatient. POPULATION: Seventy-nine patients aged between 18 and 77 years with SCI in a first rehabilitation period or follow-up. METHODS: Patients were asked to complete Short Form-36 and Incontinence Quality of Life questionnaires and a medical information form. Independent samples t-tests and ANOVA were used to compare scores between groups. RESULTS: The response rate was 71 out of 79 (89%; 51 males and 20 females). 16 paraplegic and 4 tetraplegic patients were chronic, 29 paraplegic and 22 tetraplegic patients were in rehabilitation therapy or had finished this treatment recently. The paraplegic group had a significantly better Short Form-36 total score and emotional function score, while the tetraplegic group had a significantly better Incontinence Quality of Life total score and avoidance and limiting behavior score. The paraplegic patients with 0-1 nocturnal bladder emptying had better Short Form-36-derived Quality of Life than those with ≥2 emptying. Quality of Life score was not associated with gender, leg oedema, incontinence, or acute/chronic group. Incontinence Quality of Life score was significantly better for patients with incomplete spinal cord injury. Fully completed questionnaires were returned by 36 patients; at least 1 item was missing for 35 participants. CONCLUSIONS: General Short Form-36-derived Quality of Life was better for the paraplegic population. Incontinence-related Quality of Life was better in tetraplegic patients, most of whom used suprapubic catheterization. Paraplegic patients had compromised sleep and Quality of Life when the patient had to wake up two or more times at night to empty the bladder by voiding or intermittent catheterization. The high number of incomplete responders indicates the shortcomings of Quality-of-Life questionnaires for wheelchair-bound patients with spinal cord injury. CLINICAL REHABILITATION IMPACT: The use of suprapubic catheterization should be considered to improve Quality of Life for tetraplegic patients. For paraplegic patients, we must focus urological policy on aiming to reduce the number of nighttime bladder emptying to one or none.

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.

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.

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.

Low feasibility of in vitro matured oocytes originating from cumulus complexes found during ovarian tissue preparation at the moment of gender confirmation surgery and during testosterone treatment for fertility preservation in transgender men.

OBJECTIVE: To study the feasibility of in vitro maturation of ovarian tissue oocytes for fertility preservation in transgender men on testosterone treatment. DESIGN: Cross-sectional study SETTING: University hospital PATIENT(S): Eighty-three transgender men enrolled from November 2015 to January 2019 INTERVENTION(S): In vitro maturation of cumulus-oocyte complexes (COCs) harvested at the time of gender confirmation surgery, and fertilization through intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): In vitro maturation, fertilization, and blastulation rates; comparison of morphokinetics with vitrified-warmed oocytes; and analysis of the genetic profiles of embryos. SECONDARY OUTCOMES: association between serum hormone levels; COCs' morphologic characteristics, and vitrification rate. RESULT(S): All participants were on testosterone treatment for a median of 83 (64[Quartile 1]; 113.2[Quartile 2]) weeks. A total of 1,903 COCs (mean per participant, 23 ± 15.8) were collected. The in vitro maturation rate was 23.8%, vitrification rate was 21.5%, and survival rate after warming was 72.6% (n = 151). Intracytoplasmic sperm injection was performed in 139 oocytes. The rate of normal fertilized oocytes was 34.5%, and 25 (52.1%) embryos reached day 3. One blastocyst was achieved on day 5. Aberrant cleavage patterns and early embryo arrest were observed in 22 (45.8%) and 44 (91.7%) zygotes, respectively. Compared with vitrified-warmed donor oocytes, a delay was observed in pronuclei disappearance, t2 (time to reach 2 cell stage) timings, and CC1 (the duration of the 1st cell cycle) and SS3 (synchronization of cleavage pattern (calculated as t8-t5) time intervals. A normal genetic pattern was seen in 42% embryos. The proportion of vitrified oocytes was negatively associated with progesterone (odds ratio, 0.76) and positively associated with antimüllerian hormone serum levels (odds ratio, 1.23). The highest vitrification rate was achieved by the morphologic characteristic 344 at day 0 and by 433 at day 2. CONCLUSION(S): Ovarian tissue oocytes matured in vitro show low developmental capacity in transgender men, when collected under testosterone treatment.

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.

Serum Glycomics on Postoperative Day 7 Are Associated With Graft Loss Within 3 Months After Liver Transplantation Regardless of Early Allograft Dysfunction.

BACKGROUND: Prediction of outcome after liver transplantation (LT) is limited by the lack of robust predictors of graft failure. In this prospective study, we aimed to define a serum glycomic signature in the first week after LT that is associated with graft loss at 3 mo after LT. METHODS: Patients were included between January 1, 2011, and February 28, 2017. Glycomic analysis was performed using DNA sequencer-associated fluorophore-associated capillary electrophoresis on a serum sample 1 wk after LT. Making use of Lasso regression, an optimal glycomic signature was identified associated with 3-mo graft survival. RESULTS: In this cohort of 131 patients, graft loss at 3 mo occurred in 14 patients (11.9%). The optimal mode, called the GlycoTransplantTest, yielded an area under the curve of 0.95 for association with graft loss at 3 mo. Using an optimized cutoff for this biomarker, sensitivity was 86% and specificity 89%. Negative predictive value was 98%. Odds ratio for graft loss at 3 mo was 70.211 (P < 0.001; 95% confidence interval, 10.876-453.231). CONCLUSIONS: A serum glycomic signature is highly associated with graft loss at 3 mo. It could support decision making in early retransplantation.

The effect of early and systematic integration of palliative care in oncology on quality of life and health care use near the end of life: A randomised controlled trial.

PURPOSE: This study evaluated the effect of early integrated palliative care (PC) in oncology on quality of life (QOL) near the end of life and use of health care resources near the end of life. METHOD: Patients with advanced cancer and a life expectancy of approximately 1 year were randomly assigned to either early and systematic integration of PC into oncological care (intervention) or standard oncological care alone (control). QOL was assessed with the EORTC QLQ-C30 global health status/QOL scale and McGill Quality of Life (MQOL) Single Item Scale and Summary Scale at baseline, 12 weeks and 6 weekly thereafter until death. Use of health care resources was collected from chart review in patient's electronic medical file for patients who died while participating in the study. RESULTS: Of the 186 randomised patients, 185 participants had a baseline measurement and were analysed. By November 2017, 128 patients had died while participating in the study. When applying the terminal decline model, patients in the intervention group scored significantly higher on global health status/QOL of the EORTC QLQ C30, at 6 months (difference: 5.9 [0.06; 11.1], p = 0.03), 3 (difference: 6.8 [1.0; 12.6], p = 0.02), and 1 month (difference: 7.6 [0.7; 14.5], p = 0.03) prior to the patient's death compared to the control group. Similar results were found for the Single Item Scale and Summary Score of the MQOL. We did not observe differences in use of health care resources between groups. DISCUSSION: Early integrated palliative care in oncology is a valuable approach since it also increases QOL near the end of life and not only soon after initiation of PC.

Idiopathic inflammatory myopathy: Interrater variability in muscle biopsy reading.

OBJECTIVE: To determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis. METHODS: We developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome-related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains. RESULTS: Despite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features. CONCLUSION: The assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.

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.

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.