Indoxyl Sulfate Contributes to Impaired Height Velocity in (Pre)School Children.

Introduction: Growth failure is considered the most important clinical outcome parameter in childhood chronic kidney disease (CKD). Central to the pathophysiology of growth failure is the presence of a chronic proinflammatory state, presumed to be partly driven by the accumulation of uremic toxins. In this study, we assessed the association between uremic toxin concentrations and height velocity in a longitudinal multicentric prospective pediatric CKD cohort of (pre)school-aged children and children during pubertal stages. Methods: In a prospective, multicentric observational study, a selection of uremic toxin levels of children (aged 0-18 years) with CKD stage 1 to 5D was assessed every 3 months (maximum 2 years) along with clinical growth parameters. Linear mixed models with a random slope for age and a random intercept for child were fitted for height (in cm and SD scores [SDS]). A piecewise linear association between age and height was assumed. Results: Data analysis included data from 560 visits of 81 children (median age 9.4 years; 2/3 male). In (pre)school aged children (aged 2-12 years), a 10% increase in concurrent indoxyl sulfate (IxS, total) concentration resulted in an estimated mean height velocity decrease of 0.002 SDS/yr (P < 0.05), given that CKD stage, growth hormone (GH), bicarbonate concentration, and dietary protein intake were held constant. No significant association with height velocity was found in children during pubertal stages (aged >12 years). Conclusion: The present study demonstrated that, especially IxS contributes to a lower height velocity in (pre)school children, whereas we could not find a role for uremic toxins with height velocity during pubertal stages.

A multi-centre randomized controlled trial comparing connective tissue graft with collagen matrix to increase soft tissue thickness at the buccal aspect of single implants: 3-Year results.

AIM: To compare connective tissue graft (CTG) with collagen matrix (CMX) in terms of increase in buccal soft tissue profile (BSP) when applied at single implant sites. MATERIALS AND METHODS: Patients with a single tooth gap in the anterior maxilla and horizontal mucosa defect were enrolled in a multi-centre randomized controlled trial. All were fully healed sites with a bucco-palatal bone dimension of at least 6 mm, and received an immediately restored single implant using a full digital workflow. Patients were randomly allocated to the control (CTG) or test group (CMX: Geistlich Fibro-Gide, Geistlich Pharma AG, Wolhusen, Switzerland) to increase buccal soft tissue thickness. Primary endpoints were increase in BSP at T1 (immediately postop), T2 (3 months), T3 (1 year) and T4 (3 years) based on superimposed digital surface models. Secondary endpoints included patient-reported, clinical and aesthetic outcomes. RESULTS: Thirty patients were included per group (control group: 15 males, 15 females, mean age 50.1 years; test group: 14 males, 16 females, mean age 48.2 years) and 50 could be re-examined at T4. The changes in BSP over time were significantly different between the groups (p < .001). At T4, the estimated mean increase in BSP amounted to 0.83 mm (95% confidence interval [CI]: 0.58-1.08) in the control group and 0.48 mm (95% CI: 0.22-0.73) in the test group. The estimated mean difference of 0.35 mm (95% CI: 0.06-0.65) in favour of the control group was significant (p = .021). No significant differences between the groups could be observed in terms of patients' aesthetic satisfaction (p = .563), probing depth (p = .286), plaque (p = .676), bleeding on probing (p = .732), midfacial recession (p = .667), Pink Esthetic Score (p = .366) and Mucosal Scarring Index (p = .438). However, CMX resulted in significantly more marginal bone loss (-0.43 mm; 95% CI: -0.77 to -0.09; p = .015) than CTG. CONCLUSIONS: CTG was more effective in increasing buccal soft tissue profile and resulted in less marginal bone loss than CMX. Therefore, CTG remains the gold standard to increase soft tissue thickness at implant sites. CLINICAL TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT04210596).

Epidemiological characteristics and outcome of viral respiratory tract infections in the first year after allogeneic hematopoietic cell transplantation.

Adverse outcomes of viral respiratory tract infections (RTI) have been reported in recipients of allogeneic hematopoietic cell transplantation. Using a laboratory-developed multiparameter PCR in a consecutive series of 242 patients, we found the highest incidence of viral RTI in the pre-engraftment phase. The occurrence of multiple episodes of viral RTI or viral pneumonia was significantly associated with a higher hazard of non-relapse mortality in the first year after transplantation. We observed a 90-day mortality of 19.7% after viral RTI, which was significantly different between patient groups stratified according to the ISI score.

A multi-centre randomized controlled trial on alveolar ridge preservation with immediate or delayed implant placement: Need for soft-tissue augmentation.

AIM: To assess the impact of the timing of implant placement following alveolar ridge preservation (ARP) on the need for soft-tissue augmentation (STA) and to identify the risk factors for horizontal and vertical soft-tissue loss. MATERIALS AND METHODS: Patients with a single failing tooth in the anterior maxilla (15-25) were treated at six centres. Following tooth extraction, they were randomly allocated to the test group (immediate implant placement, IIP) or control group (delayed implant placement, DIP). ARP was performed in both groups and implants were immediately restored with an implant-supported provisional crown. Six months after tooth extraction and ARP, a panel of five blinded clinicians assessed the need for STA on the basis of anonymized clinical pictures and a digital surface model. Lack of buccal soft-tissue convexity and/or mid-facial recession qualified for STA. Pre-operative and 6-month digital surface models were superimposed to assess horizontal and vertical soft-tissue changes. RESULTS: Thirty patients were included per group (test: 20 females, 10 males, mean age 53.1; control: 15 females, 15 males, mean age 59.8). The panel deemed STA as necessary in 24.1% and 35.7% of the cases following IIP and DIP, respectively. The difference was not statistically significant (odds ratio [OR] = 1.77; 95% confidence interval [CI] [0.54-5.84]; p = .343). Loss of buccal soft-tissue profile was higher following DIP (estimated mean ratio = 1.66; 95% CI [1.10-2.52]; p = .018), as was mid-facial recession (mean difference [MD] = 0.47 mm; 95% CI [0.12-0.83]; p = .011). Besides DIP, regression analysis identified soft-tissue thickness (-0.57; 95% CI [-1.14 to -0.01]; p = .045) and buccal bone dehiscence (0.17; 95% CI [0.01-0.34]; p = .045) as additional risk factors for mid-facial recession. Surgeons found IIP significantly more difficult than DIP (visual analogue scale MD = -34.57; 95% CI [-48.79 to -20.36]; p < .001). CONCLUSIONS: This multi-centre randomized controlled trial failed to demonstrate a significant difference in the need for STA between IIP and DIP when judged by a panel of blinded clinicians. Based on objective soft-tissue changes, patients with thin buccal soft tissues, with a buccal bone dehiscence and treated with a delayed approach appeared particularly prone to soft-tissue loss.

In Vitro Investigation into the Effect of Cryopreservation on the Mechanical Characteristics of Dental Hard Tissues.

Previous research has reported on hidden damage within the dentin introduced by cryopreservation, but the effect on the mechanical properties of the hard tissues at tooth level remains unclear. The main objective of this study is to investigate the effect of cryopreservation on the mechanical properties of teeth. A matched sample of 234 premolars of 117 children (9 ≤ age ≤ 16 years), bilaterally extracted for orthodontic reasons, were included. For each child, one tooth was randomly allocated to the cryopreservation group and the contralateral tooth was assigned to the control group. Static compression tests were performed to determine load to failure, stiffness, and toughness. In a subgroup of 20 teeth, a cyclic preloading or chewing simulation was performed. Additionally, the fracture mode was determined, and the microstructure of the fractured surfaces was examined using a scanning electron microscope (SEM). Linear mixed model analyses could not detect a statistical difference in the mean load to failure (p = 0.549), mean toughness (p = 0.968), or mean stiffness (p = 0.150) between cryopreserved and non-cryopreserved teeth. No significant difference in load to failure after cyclic preloading was detected between groups (p = 0.734). SEM analysis revealed comparable fracture characteristics between groups. It is concluded that cryopreservation does not affect the mean load to failure, stiffness, or toughness of teeth, indicating that hidden damage in the dentin is not critical at tooth level.

Factors Related to Police Reporting in Sexual Assault Care Centers: Are We Underestimating the Role of Support Persons?

Few victims of sexual assault (SA) report to the police. Research on the role of support persons in victims' reporting is sparse. We address this gap by examining the association of victim, assailant, victimization incident, and support characteristics with reporting rates among victims attending sexual assault care centers (SACCs). Logistic regression results show that type of SA, delay between SA and presentation at SACC, and presence of an informal support person at SACC and SACC site are significantly associated with police reporting. These findings reveal the importance of targeting victims' support persons to alter reporting behavior among SA victims.

Infectious diarrhea after allogeneic hematopoietic cell transplantation assessed by a multiplex polymerase chain reaction assay.

OBJECTIVES: To determine the incidence of infectious diarrhea after allogeneic hematopoietic cell transplantation (HCT) using a multiplex polymerase chain reaction assay and assess risk factors for developing infectious diarrhea. METHODS: This was a single-center retrospective study of 140 consecutive allogeneic HCT recipients. Infectious diarrhea was assessed using a laboratory-developed multiplex polymerase chain reaction the first year after transplantation. RESULTS: The incidence rate of infectious diarrhea episodes was 47 per 100 person-years, with the highest rate observed in the pre-engraftment phase. Most episodes were seen as nosocomial infections (38%) and most affected patients (82%) had only one episode of infectious diarrhea. The cumulative incidence of at least one episode of infectious diarrhea was 32% after 1 year. Nonrelapse mortality was higher in transplant recipients with at least one episode of infectious diarrhea (hazard ratio (HR) 2.02, 95% CI = 1.07-3.80). The most frequently observed pathogens were Clostridium difficile, adenovirus, Enteropathogenic Escherichia coli, and Campylobacter jejuni. Patients with acute lower gastrointestinal graft-vs-host disease stage 3 or 4 (HR 3.68, 95% CI = 1.57-8.63) conferred a higher risk for a first infectious diarrhea episode. CONCLUSION: Infectious diarrhea after allogeneic HCT was seen in about one-third of the patients, mostly as nosocomial infection in the pre-engraftment phase.

The Euroflow PID Orientation Tube in the diagnostic workup of primary immunodeficiency: Daily practice performance in a tertiary university hospital.

Introduction: Multiparameter flow cytometry (FCM) immunophenotyping is an important tool in the diagnostic screening and classification of primary immunodeficiencies (PIDs). The EuroFlow Consortium recently developed the PID Orientation Tube (PIDOT) as a universal screening tool to identify lymphoid-PID in suspicious patients. Although PIDOT can identify different lymphoid-PIDs with high sensitivity, clinical validation in a broad spectrum of patients with suspicion of PID is missing. In this study, we investigated the diagnostic performance of PIDOT, as part of the EuroFlow diagnostic screening algorithm for lymphoid-PID, in a daily practice at a tertiary reference center for PID. Methods: PIDOT was tested in 887 consecutive patients suspicious of PID at the Ghent University Hospital, Belgium. Patients were classified into distinct subgroups of lymphoid-PID vs. non-PID disease controls (non-PID DCs), according to the IUIS and ESID criteria. For the clinical validation of PIDOT, comprehensive characterization of the lymphoid defects was performed, together with the identification of the most discriminative cell subsets to distinguish lymphoid-PID from non-PID DCs. Next, a decision-tree algorithm was designed to guide subsequent FCM analyses. Results: The mean number of lymphoid defects detected by PIDOT in blood was 2.87 times higher in lymphoid-PID patients vs. non-PID DCs (p < 0.001), resulting in an overall sensitivity and specificity of 87% and 62% to detect severe combined immunodeficiency (SCID), combined immunodeficiency with associated or syndromic features (CID), immune dysregulation disorder (ID), and common variable immunodeficiency (CVID). The most discriminative populations were total memory and switched memory B cells, total T cells, TCD4+cells, and naive TCD4+cells, together with serum immunoglobulin levels. Based on these findings, a decision-tree algorithm was designed to guide further FCM analyses, which resulted in an overall sensitivity and specificity for all lymphoid-PIDs of 86% and 82%, respectively. Conclusion: Altogether, our findings confirm that PIDOT is a powerful tool for the diagnostic screening of lymphoid-PID, particularly to discriminate (S)CID, ID, and CVID patients from other patients suspicious of PID. The combination of PIDOT and serum immunoglobulin levels provides an efficient guide for further immunophenotypic FCM analyses, complementary to functional and genetic assays, for accurate PID diagnostics.

Effects of a theory-based advance care planning intervention for nursing homes: A cluster randomized controlled trial.

BACKGROUND: Uptake of advance care planning in routine nursing home care is low. Through extensive literature review, theoretical development, and stakeholder involvement, we developed the ACP+ intervention. AIMS: To evaluate the effects of ACP+ on the knowledge and self-efficacy (confidence in own skills) of nursing home care staff concerning advance care planning. DESIGN: Cluster randomized controlled trial, conducted between February 2018 and January 2019 (NCT03521206, clinicaltrials.gov). ACP+ is a multicomponent intervention aimed at training and supporting nursing home staff and management in implementing advance care planning in nursing home practice through a train-the-trainer approach over 8 months. Fourteen nursing homes were randomized using a matched-pairing strategy, seven received ACP+, seven followed usual practice. Analyses (intention-to-treat) involved linear mixed models. SETTING/PARTICIPANTS: Nursing homes in Flanders (Belgium). RESULTS: 694 of 1017 care staff (68% response rate) at baseline and 491 of 989 care staff (50%) post-intervention (8 months) returned questionnaires. Post-intervention, care staff's self-efficacy concerning advance care planning was significantly higher in the intervention than in the control group (baseline-adjusted mean difference 0.57; 95% CI 0.20-0.94; p = 0.003; Cohen's d = 0.30). Advance care planning knowledge (95% CI 0.95-1.15; p = 0.339; ratio: 1.04) did not differ significantly between groups. CONCLUSIONS: The ACP+ intervention for nursing homes improved care staff's self-efficacy but not their knowledge concerning advance care planning. Considering the comprehensive and multi-component approach used, these effects were smaller than expected. Reasons for this may be related to the chosen follow-up period, outcomes and measurements, or to the intervention itself and its implementation.

Neonatal magnesium levels are safe after maternal MgSO4 administration: a comparison between unexposed preterm neonates and neonates exposed for fetal neuroprotection or maternal eclampsia prevention-a cohort study.

To objective of this study was to compare neonatal magnesemia in the first 15 days of neonatal life between three groups: a control group not exposed to MgSO4, a neuroprotection group, and an eclampsia prevention group, and to explore its associations with child outcomes. A retrospective single-centre cohort study was performed in a tertiary care setting. Infants admitted at the neonatal intensive care unit born between 24 and 32 weeks' gestation, regardless of etiology of preterm birth, were included. The mean outcome measure was neonatal magnesemia (mmol/L). Linear mixed regression of neonatal magnesemia on exposure group and day of life was done. Generalised estimating equation models of child outcomes on neonatal magnesemia according to exposure group and day of life were made. The analyses showed that in neonatal magnesemia is significantly higher in the preeclampsia group compared to the control and neuroprotection groups. On the day of birth, this is irrespective of maternal magnesemia (preeclampsia vs control groups), and the maternal total dose or duration of MgSO4 administration (preeclampsia vs neuroprotection group). No differences were found in short-term composite outcome between the three groups. CONCLUSION: We found mean differences in neonatal magnesemia between children not exposed to MgSO4 antenatally, children exposed for fetal neuroprotection, and children exposed for maternal eclampsia prevention. A 4-g loading and 1-g/h maintenance doses, for fetal neuroprotection and eclampsia prevention, appear to be safe on the short term for the neonate. WHAT IS KNOWN: • Magnesium sulphate is a valuable medicine in obstetrics. The main indications are prevention of eclampsia and fetal neuroprotection. The most used dosage is a 4- or 6-g loading dose and a 1- or 2-g per h maintenance dose. It reduces neuromotor disabilities in extreme-to-moderate preterm born children. WHAT IS NEW: • Maternal concentrations are supraphysiological and the maternal total dose can be high. Concentrations in neonates appear to remain in safe ranges. A dosage of 4-g loading and 1 g/h seems safe for the preterm neonate on the short term.

The relationship between circulating hormone levels, bone turnover markers and skeletal development in healthy boys differs according to maturation stage.

INTRODUCTION: This study investigates peri-pubertal changes in bone turnover markers, Wnt-signalling markers, insulin-like growth factor-1 (IGF-1) and sex steroid levels, and how they reflect skeletal development in peri-pubertal boys. MATERIALS AND METHODS: Population-based study in 118 peri-pubertal boys from the NINIOS cohort (age range at baseline 5.1-17.3 years) with repeated measurements at baseline and after two years. Serum levels of the classical bone turnover markers (BTM) procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks, as well as sex-hormone binding globulin, IGF-1, osteoprotegerin, sclerostin and dickkopf-1 were measured using immunoassays. Sex steroids (estradiol, testosterone, and androstenedione) were measured using mass spectrometry and free fractions calculated. Dual energy x-ray absorptiometry was used for bone measurements at the lumbar spine and whole body. Volumetric bone parameters and bone geometry at the proximal and distal radius were assessed by peripheral QCT. Pubertal development was categorized based on Tanner staging. RESULTS: During puberty, sex steroid and IGF-1-levels along with most parameters of bone mass and bone size increased every next Tanner stage. In contrast, classical bone turnover markers and sclerostin peaked around mid-puberty, with subsequent declines towards adult values in late puberty. Especially classical BTM and sex steroid levels showed consistent associations with areal and volumetric bone parameters and bone geometry. However, observed associations differed markedly according to pubertal stage and skeletal site. CONCLUSION: Serum levels of sex steroids, IGF-1 and bone metabolism markers reflect skeletal development in peri-pubertal boys. However, skeletal development during puberty is nonlinear, and the relations between skeletal indices and hormonal parameters are nonlinear as well, and dependent on the respective maturation stage and skeletal site.

Assessment of a Novel Fixation Method of a Frameless Intrauterine Contraceptive Device Inserted during Cesarean Delivery as a Means of Preventing Displacements and Expulsions: A Prospective Observational Study.

The primary objective of this study was to assess the novel fixation method of a frameless copper-releasing intrauterine device inserted following placental delivery during cesarean section and analyze its impact in reducing device displacement and expulsion during and after uterine involution. We hypothesized that the dual-anchoring technique could reduce the risk of intrauterine device displacement and expulsion during and after the uterine involution. The study was conducted at the Gazi University Medicine Faculty Hospital in Ankara, Turkey. Twenty-one pregnant women were enrolled. Insertion was performed following placental removal. To confirm the proper placement and good retention of the device, the distance between the fundal serosa (S) and device anchor knot (A) was measured (S-A) during follow-ups, by ultrasound. There were significant differences in the S-A, as observed by ultrasound at discharge and at 6 weeks post-delivery, which is consistent with the tissue contractions associated with uterine involution. Notwithstanding the uterine involution, no device displacements or expulsions occurred, which indicated a good retention of the frameless device. This innovative retention method of the frameless intrauterine device ensures a well-tolerated, long-term contraception, allowing for immediate contraception and proper pregnancy spacing for cesarean scar healing, and overcomes the issue of expulsion encountered with conventional intrauterine systems.

The impact of multimorbidity patterns on health-related quality of life in the general population: results of the Belgian Health Interview Survey.

BACKGROUND: Chronic diseases and multimorbidity are a major cause of disease burden-for patients, caregivers, and society. Little is known however about potential interaction effects between specific disease combinations. Besides an additive effect, the presence of multiple conditions could also act synergistically or antagonistically regarding the impact on patients' health-related quality of life (HRQoL). The aim was to estimate the impact of coexisting chronic diseases on HRQoL of the adult general Belgian population. METHODS: The Belgian Health Interview Survey 2018 provided data on self-reported chronic conditions and HRQoL (EQ-5D-5L) for a nationally representative sample. Linear mixed models were used to analyze two-way and three-way interactions of disease combinations on HRQoL. RESULTS: Multimorbidity had a prevalence of 46.7% (≥ 2 conditions) and 29.7% (≥ 3 conditions). HRQoL decreased considerably with the presence of multiple chronic diseases. 14 out of 41 dyad combinations and 5 out of 13 triad combinations showed significant interactions, with a dominant presence of negative/synergistic effects. Positive/antagonistic effects were found in more subjective chronic diseases such as depression and chronic fatigue. Conditions appearing the most frequently in significant disease pair interactions were dorsopathies, respiratory diseases, and arthropathies. CONCLUSIONS: Diverse multimorbidity patterns, both dyads and triads, were synergistically or antagonistically associated with lower HRQoL. Tackling the burden of multimorbidity is needed, especially because most disease combinations affect each other synergistically, resulting in a greater reduction in HRQoL. Further knowledge about those multimorbidity patterns with a greater impact on HRQoL is needed to better understand disease burden beyond mortality and morbidity data.

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.

Magnetic resonance imaging findings in the normal pediatric sacroiliac joint space that can simulate disease.

BACKGROUND: Magnetic resonance imaging (MRI) features of active sacroiliac joint inflammation include joint space fluid and enhancement, but it is unclear to what extent these are present in normal children. OBJECTIVE: To describe normal MRI appearances of pediatric sacroiliac joint spaces in boys and girls of varying ages. MATERIALS AND METHODS: In this ethics-approved prospective study, 251 children (119 boys, 132 girls; mean age: 12.4 years, range: 6.1-18.0 years), had both oblique-coronal T1-weighted and short tau inversion recovery (STIR) sacroiliac joint MRI. Of these, 127 were imaged for other reasons and had asymptomatic sacroiliac joints ("normal cohort") while 124 had low back pain with no features of sacroiliitis on initial clinical MRI review ("low-back-pain cohort"). Post-gadolinium T1-weighted sequences were available in 16/127 normal and 124/124 low-back-pain subjects. Three experienced radiologists scored high signal in the sacroiliac joint space on STIR (score 0=absent; 1=high signal compared to normal bone marrow present anywhere in the joint but not as bright as fluid [compared to vessels, cerebrospinal fluid]; 2=definite fluid signal in part of the joint; 3=definite fluid signal, entire vertical height, majority of slices) and, when available, joint space post-contrast enhancement (0=no high signal/enhancement; 1=thin, symmetrical, mildly increased linear high signal present in the joint space; 2=focal, thick or intense enhancement). Associations between joint signal scores, age, gender and sacral apophyseal closure were analysed. RESULTS: Increased signal on STIR (score 1-3) was present in 74.7% of pediatric sacroiliac joint spaces, as intense as fluid in 18.4%. There was no significant difference in proportion by gender, side or cohort, but girls showed peak signal earlier than boys (10 years old vs. 12 years old, respectively). On post-gadolinium T1-weighted sequences, a thin rim of increased signal was nearly universally seen in sacroiliac joint spaces without focal, intense or thick post-contrast enhancement. CONCLUSION: Sacroiliac joint spaces of most children demonstrate mildly increased signal on STIR, compared to normal bone marrow, and thin rim-like enhancement on post-contrast T1 images, likely related to cartilage. These findings should not be confused with sacroiliitis.

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.

Early peri-implant bone loss as a predictor for peri-implantitis: A 10-year prospective cohort study.

PURPOSE: To evaluate the effect of early bone loss (EBL), on long-term bone stability and future peri-implantitis development. MATERIALS AND METHODS: Patients referred for implant placement between 2005 and 2009 were consecutively treated and followed for 10 years. After 10 years, patients were invited for a scientific diagnostic visit to evaluate implant survival and bone loss. Bone level changes were compared with baseline. Non-parametric testing was performed in cross-tabs (Pearson Chi-square and Fishers's exact test). Kaplan-Meier-estimated survival curves were plotted for different thresholds for EBL at different timepoints. Generalized linear mixed models with binomial distribution and logit link for peri-implantitis were fitted. An adjusted logistic mixed model was made to evaluate peri-implantitis, in relation with smoking status, history of periodontitis, and EBL > 0.5 mm. RESULTS: Four hundred and seven patients (mean age of 64.86 years [range 28-92, SD 10.11]), with 1482 implants, responded to the 10-year recall invitation. After an average follow-up time of 10.66 years (range 10-14, SD 0.87), implant survival was 94.74%. Mean crestal bone loss after 10 years was 0.81 mm (SD 1.58, range 0.00-17.00). One hundred and seventy five implants in 76 patients had peri-implantitis (11.8% on implant level, 18.7% on patient level). EBL of 0.5, 1, and 2 mm were significant predictors for peri-implantitis and implant loss after 10 years. Implants with EBL ≥0.5 mm during the first year of function showed a 5.43 times higher odds for future peri-implantitis development. Probability in developing peri-implantitis was 52.06% when smoking, Periodontal history and EBL of >0.5 mm was combined. CONCLUSION: The present study suggests that EBL is a predictor for long-term peri-implant pathology, with a significant higher risk for peri-implantitis when early bone loss exceeds the thresholds of 0.5 and 1 mm, especially when additional risk factors such as smoking or susceptibility for periodontal disease prior to implant treatment are present. Clinical trial registration number B670201524796.

Normal subchondral high T2 signal on MRI mimicking sacroiliitis in children: frequency, age distribution, and relationship to skeletal maturity.

OBJECTIVES: To determine patterns of variation of subchondral T2 signal changes in pediatric sacroiliac joints (SIJ) by location, age, sex, and sacral apophyseal closure. METHODS: MRI of 502 SIJ in 251 children (132 girls), mean age 12.4 years (range 6.1-18.0), was obtained with parental informed consent. One hundred twenty-seven out of 251 had asymptomatic joints and were imaged for non-rheumatologic reasons, and 124 had low back pain but no sign of sacroiliitis on initial clinical MRI review. After calibration, three subspecialist radiologists independently scored subchondral signal changes on fat-suppressed fluid-sensitive sequences from 0 to 3 in 4 locations, and graded the degree of closure of sacral segmental apophyses. Associations between patient age, sex, signal changes, and apophyseal closure were analyzed. RESULTS: Rim-like subchondral increased T2 signal or "flaring" was much more common at sacral than iliac SIJ margins (72% vs 16%, p < 0.001) and was symmetrical in > 90% of children. Iliac flaring scores were always lower than sacral, except for 1 child. Signal changes decreased as sacral apophyses closed, and were seen in < 20% of subjects with fully closed apophyses. Signal changes were more frequent in boys, and peaked in intensity later than for girls (ages 8-12 vs. 7-10). Subchondral signal in iliac crests was high throughout childhood and did not correlate with other locations. CONCLUSIONS: Subchondral T2 "flaring" is common at SIJ of prepubertal children and is generally sacral-predominant and symmetrical. Flaring that is asymmetrical, greater in ilium than sacrum, or intense in a teenager with closed apophyses, is unusual for normal children and raises concern for pathologic bone marrow edema. KEY POINTS: • A rim of subchondral high T2 signal is commonly observed on MRI at pediatric sacroiliac joints, primarily on the sacral side before segmental apophyseal closure, and should not be confused with pathology. • Unlike subchondral signal changes elsewhere, high T2 signal underlying the iliac crest apophyses is a near-universal normal finding in children that usually persists throughout adolescence. • The following patterns are unusual in normal children and are suspicious for pathology: definite iliac flaring, iliac flaring more intense than sacral flaring, left-right difference in flaring, definite flaring of any pattern in teenagers after sacral apophyseal closure.

Infectious diseases epidemiology, quantitative methodology, and clinical research in the midst of the COVID-19 pandemic: Perspective from a European country.

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy.