The reliability and validity of the juvenile idiopathic arthritis magnetic resonance scoring system for temporomandibular joints.

In children with juvenile idiopathic arthritis (JIA), the temporomandibular joint (TMJ) can be involved. To prevent TMJ damage due to inflammation, early recognition is important, for which contrast-enhanced magnetic resonance imaging (MRI) is the gold standard. In this study, the interobserver reliability and construct validity of the Juvenile Idiopathic Arthritis Magnetic Resonance Scoring System for Temporomandibular Joints (JAMRIS-TMJ) was assessed. Two radiologists independently examined 38 MRIs using the JAMRIS-TMJ scoring system. Inter-observer reliability was assessed by Cohen's (weighted) kappa (κ), 95% confidence intervals (CIs) and absolute agreement (%). Construct validity was assessed by correlation between the JAMRIS-TMJ items and TMJ involvement, active maximum interincisal mouth opening (AMIO), and anterior maximum voluntary bite force (AMVBF). The interobserver reliability for the JAMRIS-TMJ items varied from poor to good (κ = 0.18-0.61). Joint enhancement had the highest reliability (κ = 0.61). Correlations were found between TMJ involvement, AMIO, and the JAMRIS-TMJ items, although variation between radiologists and TMJ side existed. No correlation was found between AMVBF and the JAMRIS-TMJ items for both radiologists. The strongest correlations were found between most of the JAMRIS-TMJ items and AMIO. Our findings support the utility of AMIO as a clinical measure of TMJ status in children with JIA.

Did aetiology matter in illness duration and complications in patients presenting in primary care with acute respiratory tract infections early in the COVID-19 pandemic: An observational study in nine countries.

BACKGROUND: Despite considerable research into COVID-19 sequelae, little is known about differences in illness duration and complications in patients presenting in primary care with symptoms of acute respiratory tract infections (RTI) that are and are not attributed to SARS-CoV-2 infection. OBJECTIVE: To explore whether aetiology impacted course of illness and prediction of complications in patients presenting in primary care with symptoms of RTI early in the COVID-19 pandemic. METHODS: Between April 2020-March 2021 general practitioners from nine European countries recruited consecutively contacting patients with RTI symptoms. At baseline, an oropharyngeal-nasal swab was obtained for aetiology determination using PCR after follow-up of 28 days. Time to self-reported recovery was analysed with Kaplan-Meier curves. Predictors (baseline variables of demographics, patient and disease characteristics) of a complicated course (composite of hospital admission and persisting signs/symptoms at 28 days follow-up) were explored with logistic regression modelling. RESULTS: Of 855 patients with RTI symptoms, 237 (27.7%) tested SARS-CoV-2 positive. The proportion not feeling fully recovered (15.6% vs 18.1%, p = 0.39), reporting being extremely tired (9.7% vs 12.8%, p = 0.21), and not having returned to usual daily activities (18.1% vs 14.4%, p = 0.18) at day 28 were comparable between SARS-CoV-2 positive (n = 237) and negative (n = 618) groups. However, among those feeling fully recovered (SARS-CoV-2 positive: 200 patients, SARS-CoV-2 negative: 506 patients), time to full recovery was significantly longer in SARS-CoV-2 patients (10.6 vs 7.7 days, p < 0.001). We found no evidence that predictors of a complicated course differed between groups (p = 0.07). CONCLUSION: Early in the pandemic, the proportion of patients not feeling fully recovered by 28 days was similar between SARS-CoV-2 positive and negative patients presenting in primary care with RTI symptoms, but it took somewhat longer for SARS-CoV-2 patients to feel fully recovered. More research is needed on predictors of a complicated course in RTI.

Our primary care-based observational study found that recovery by 28 days was comparable between SARS-CoV-2 positive and negative RTI patients.Future research is needed to unravel which host- and pathogen-related profiles are associated with higher risk of complications and persisting symptoms among patients presenting in primary care with RTI symptoms.

Reliability of mandibular range of motion measurements in healthy children.

BACKGROUND: Mandibular range of motion (MROM) variables are widely used to evaluate oral function. OBJECTIVE: The aim of this study was to establish the reliability of MROM variables in healthy children. METHODS: In this cross-sectional study, healthy children were examined 2 weeks apart. The following MROM variables were established: active maximum interincisal opening (AMIO), passive maximum interincisal opening (PMIO), protrusion and left and right laterotrusion. The reliability of the MROM measurements was determined by analysing the intra-class correlation coefficient (ICC), standard error of measurement (SEM), smallest detectable change (SDC) and limits of agreement (LoA). RESULTS: A total of 167 healthy children were examined. The ICC indicated good reliability for AMIO (0.885); excellent reliability for PMIO (0.925); and moderate reliability for protrusion (0.578), laterotrusion left (0.601) and laterotrusion right (0.634). The SDC was 0.9 mm for AMIO, 0.4 mm for PMIO, 2.2 mm for protrusion, 1.6 mm for laterotrusion left and 1.4 mm for laterotrusion right. The LoA was -5.67 to 5.82 for AMIO, -3.90 to 3.57 for PMIO, -3.89 to 3.55 for protrusion, -2.99 to 2.77 for laterotrusion left, and - 2.71 to 2.77 for laterotrusion right. CONCLUSIONS: AMIO and PMIO measurements are both highly reliable in healthy children. The low SDC indicate that AMIO and PMIO are promising longitudinal measurements. Protrusion and laterotrusion measurements had moderate reliability. These results support our clinical recommendation to measure AMIO rather than PMIO, as PMIO is more difficult and more time-consuming to perform than AMIO.

Association between bronchopulmonary dysplasia severity and its risk factors and long-term outcomes in three definitions: a historical cohort study.

OBJECTIVE: To compare the association of the severity categories of the 2001-National Institutes of Health (NIH), the 2018-NIH and the 2019-Jensen bronchopulmonary dysplasia (BPD) definitions with neurodevelopmental and respiratory outcomes at 2 and 5 years' corrected age (CA), and several BPD risk factors. DESIGN: Single-centre historical cohort study with retrospective data collection. SETTING: Infants born between 2009 and 2015 at the Amsterdam University Medical Centers, location Amsterdam Medical Center. PATIENTS: Preterm infants born at gestational age (GA) <30 weeks and surviving up to 36 weeks' postmenstrual age. INTERVENTIONS: Perinatal characteristics, (social) demographics and comorbidities were collected from the electronic patient records. MAIN OUTCOME MEASURES: The primary outcomes were neurodevelopmental impairment (NDI) or late death, and respiratory morbidity at 2 and 5 years' CA. Using logistic regression and Brier scores, we investigated if the ordinal grade severity is associated with incremental increase of adverse long-term outcomes. RESULTS: 584 preterm infants (median GA: 28.1 weeks) were included and classified according to the three BPD definitions. None of the definitions showed a clear ordinal incremental increase of risk for any of the outcomes with increasing severity classification. No significant differences were found between the three BPD definitions (Brier scores 0.169-0.230). Respiratory interventions, but not GA, birth weight or small for GA, showed an ordinal relationship with BPD severity in all three BPD definitions. CONCLUSION: The severity classification of three BPD definitions showed low accuracy of the probability forecast on NDI or late death and respiratory morbidity at 2 and 5 years' CA, with no differences between the definitions.

Topical or oral antibiotics in childhood acute otitis media and ear discharge: a randomized controlled non-inferiority trial.

BACKGROUND: Current guidance suggests oral antibiotics can be considered for children with acute otitis media (AOM) and ear discharge, but there is an absence of evidence regarding the relative effectiveness of antibiotic-corticosteroid eardrops. AIM: To establish whether antibiotic-corticosteroid eardrops are non-inferior to oral antibiotics in children with AOM and ear discharge. DESIGN AND SETTING: Open randomized controlled non-inferiority trial set in Dutch primary care. METHODS: Children were randomized to hydrocortisone-bacitracin-colistin eardrops (five drops, three times per day in the discharging ear(s)) or amoxicillin suspension (50 mg per kilogram of body weight per day, divided over three doses administered orally) for 7 days. The primary outcome was the proportion of children with resolution of ear pain and fever at day 3. RESULTS: Between December 2017 and March 2023, 58 of the planned 350 children were recruited due to slow accrual for various reasons. Children assigned to eardrops (n = 26) had lower resolution rates of ear pain and fever at 3 days compared to those receiving oral antibiotics (n = 31): 42% vs 65%; adjusted risk difference 20.3%, 95% confidence interval -5.3% to 41.9%), longer parent-reported ear discharge (6 vs 3 days; P = .04), and slightly higher mean ear pain scores (Likert scale 0-6) over days 1-3 (2.1 vs 1.4, P = .02), but received fewer oral antibiotic courses in 3months (11 for 25 children vs 33 for 30 children), and had less GI upset and rash (12% vs 32% and 8% vs 16%, respectively). CONCLUSION: Early termination stopped us from determining non-inferiority of antibiotic-corticosteroid eardrops. Our limited data, requiring confirmation, suggest that oral antibiotics may be more effective than antibiotic-corticosteroid eardrops in resolving symptoms and shortening the duration of ear discharge.

Effect of dupilumab on asthma and aeroallergen sensitization in pediatric atopic dermatitis patients: Results of the BioDay registry.

BACKGROUND: Atopic dermatitis (AD) is frequently associated with asthma and allergic rhinitis (AR). Dupilumab is an effective treatment for pediatric AD, although the effect on atopic comorbidities in pediatric AD patients is limited. OBJECTIVE: To investigate the prevalence of asthma and AR in pediatric AD patients starting dupilumab treatment and to evaluate the effect of dupilumab on these comorbidities. METHODS: This study included pediatric AD patients (aged 3-17 years) treated with dupilumab between 2019 and 2023. Patients were screened at baseline by a pulmonologist for the presence of asthma and AR. Screening included evaluation of medical history and current symptoms, spirometry (including Forced Expiratory Volume in 1 s (FEV1)), Fractional exhaled Nitric Oxide (FeNO), and measurement of aeroallergen-specific IgE levels. In patients diagnosed with comorbid asthma and/or AR, measurements were repeated at weeks 16 and 52. Spirometry measurements, FeNO, and aeroallergen-specific IgE levels during treatment were analyzed using a covariance pattern model. RESULTS: Eighty-four patients were included. Asthma was diagnosed in 50 patients (59.5%) and AR in 72 patients (85.7%). Baseline FeNO levels were elevated in both patients with (29.0 ppb (95% CI 22.0-54.0)) and without asthma (26.0 ppb (95% CI 22.0-30.0)). During treatment, FeNO levels decreased (p < .001) and FEV1 scores increased (p < .001) in patients with asthma. In patients with asthma and/or AR, all aeroallergen-specific IgE levels decreased between 61.3% and 89.1% at 52 weeks of treatment. CONCLUSION: One year of dupilumab treatment, primarily indicated for AD, resulted in a significant improvement in comorbid asthma and a profound decrease in aeroallergen-specific IgE levels in patients with asthma and/or AR.

Patient preferences for disposable and reusable vaginal specula and their willingness to compromise in the era of climate change: A cross-sectional study.

OBJECTIVE: To evaluate patient satisfaction on gynaecological examination with metal, plastic and biobased plastic vaginal specula, and to investigate whether patients are willing to compromise on comfort for a more sustainable healthcare system. DESIGN: Cross-sectional study: population-based survey. SETTING: Gynaecological outpatient clinics in five Dutch hospitals. POPULATION: Patients during general gynaecology consultation hours. METHODS: A survey containing two questions about patient demographics, four about comfort and five about sustainability and healthcare was distributed. MAIN OUTCOME MEASURES: Comfort score (scale 1-10). SECONDARY OUTCOMES: (1) temperature, size and ease of insertion, (2) willingness to compromise for a more sustainable healthcare system. RESULTS: In all, 196 patients completed the survey. Biobased plastic vaginal specula scored significantly higher on comfort than the metal ones (mean 8.03 ± 1.65 versus 7.26 ± 1.51 respectively; P < 0.001). The biobased plastic vaginal speculum is significantly the most comfortable on temperature, whereas the metal speculum is the least comfortable (P < 0.007). Most patients are willing to compromise on comfort or are open to the reuse of disposables to contribute to a more sustainable healthcare. The majority of patients (77%) urge healthcare organisations to combat climate change. CONCLUSIONS: There is a small but statistically significant difference in favour of a biobased plastic speculum regarding comfort score, although it might be questioned whether this is clinically relevant. Furthermore, patients are willing to compromise on comfort for a more sustainable healthcare, which should be a contributing factor in speculum selection.

Diagnostic yield of a proactive strategy for early detection of cardiovascular disease versus usual care in adults with type 2 diabetes or chronic obstructive pulmonary disease in primary care in the Netherlands (RED-CVD): a multicentre, pragmatic, cluster-randomised, controlled trial.

BACKGROUND: Progressive cardiovascular diseases (eg, heart failure, atrial fibrillation, and coronary artery disease) are often diagnosed late in high-risk individuals with common comorbidities that might mimic or mask symptoms, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes. We aimed to assess whether a proactive diagnostic strategy consisting of a symptom and risk factor questionnaire and low-cost and accessible tests could increase diagnosis of progressive cardiovascular diseases in patients with COPD or type 2 diabetes in primary care. METHODS: In this multicentre, pragmatic, cluster-randomised, controlled trial (RED-CVD), 25 primary care practices in the Netherlands were randomly assigned to usual care or a proactive diagnostic strategy conducted during routine consultations and consisting of a validated symptom questionnaire, followed by physical examination, N-terminal-pro-B-type natriuretic peptide measurement, and electrocardiography. We included adults (≥18 years) with type 2 diabetes, COPD, or both, who participated in a disease management programme. Patients with an established triple diagnosis of heart failure, atrial fibrillation, and coronary artery disease were excluded. In the case of abnormal findings, further work-up or treatment was done at the discretion of the general practitioner. The primary endpoint was the number of newly diagnosed cases of heart failure, atrial fibrillation, and coronary artery disease, adjudicated by an expert clinical outcome committee using international guidelines, at 1-year follow-up, in the intention-to-treat population. FINDINGS: Between Jan 31, 2019, and Oct 7, 2021, we randomly assigned 25 primary care centres: 11 to usual care and 14 to the intervention. We included patients between June 21, 2019, and Jan 31, 2022. Following exclusion of ineligible patients and those who did not give informed consent, 1216 participants were included: 624 (51%) in the intervention group and 592 (49%) in the usual care group. The mean age of participants was 68·4 years (SD 9·4), 482 (40%) participants were female, and 734 (60%) were male. During 1 year of follow-up, 50 (8%) of 624 participants in the intervention group and 18 (3%) of 592 in the control group were newly diagnosed with heart failure, atrial fibrillation, or coronary artery disease (adjusted odds ratio 2·97 [95% CI 1·66-5·33]). This trial is registered with the Netherlands Trial Registry, NTR7360, and was completed on Jan 31, 2023. INTERPRETATION: An easy-to-use, proactive, diagnostic strategy more than doubled the number of new diagnoses of heart failure, atrial fibrillation, and coronary artery disease in patients with type 2 diabetes or COPD in primary care compared with usual care. Although the effect on patient outcomes remains to be studied, our diagnostic strategy might contribute to improved early detection and timely initiation of treatment in individuals with cardiovascular disease. FUNDING: Dutch Heart Foundation.

Salivary concentrations of secretory leukocyte protease inhibitor and matrix metallopeptidase-9 following a single bout of exercise are associated with intensity and hydration status.

AIM: To investigate the effects of exercise on salivary concentrations of inflammatory markers by analyzing a panel of 25 inflammatory markers in subjects who had participated in bicycle ergometer tests varying in workload and hydration status. METHODS: Fifteen healthy young men (20-35 years) had performed 4 different exercise protocols of 1 hour duration in a randomly assigned cross-over design, preceded by a rest protocol. Individual workloads depended on participant's pre-assessed individual maximum workload (Wmax): rest (protocol 1), 70% Wmax in hydrated (protocol 2) and dehydrated (protocol 3) state, 50% Wmax (protocol 4) and intermittent 85%/55% Wmax in 2 min blocks (protocol 5). Saliva samples were collected before (T0) and immediately after exercise (T1), and at several time points after exercise (2 hours (T3), 3 hours (T4), 6 hours (T5) and 24 hours (T6)). Secretory Leukocyte Protease Inhibitor (SLPI), Matrix Metallopeptidase-9 (MMP-9) and lactoferrin was analyzed using a commercial ELISA kit, a panel of 22 cytokines and chemokines were analyzed using a commercial multiplex immunoassay. Data was analyzed using a multilevel mixed linear model, with multiple test correction. RESULTS: Among a panel of 25 inflammatory markers, SLPI concentrations were significantly elevated immediately after exercise in all protocols compared to rest and higher concentrations reflected the intensity of exercise and hydration status. MMP-9 showed a significant increase in the 70% Wmax dehydrated, 50% Wmax and intermittent protocols. CONCLUSIONS: Salivary concentrations of SLPI and MMP-9 seem associated with exercise intensity and hydration status and may offer non-invasive biomarkers to study (local) inflammatory responses to different exercise intensities in human studies.

Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

Neuroinflammation and microthrombosis may be underlying mechanisms of brain injury after aneurysmal subarachnoid hemorrhage (aSAH), but they have not been studied in relation to each other. In postmortem brain tissue, we investigated neuroinflammation by studying the microglial and astrocyte response in the frontal cortex of 11 aSAH and 10 control patients. In a second study, we investigated the correlation between microthrombosis and microglia by studying the microglial surface area around vessels with and without microthrombosis in the frontal cortex and hippocampus of 8 other aSAH patients. In comparison with controls, we found increased numbers of microglia (mean ± SEM 50 ± 8 vs 20 ± 5 per 0.0026 mm³, p < 0.01), an increased surface area (%) of microglia (mean ± SEM 4.2 ± 0.6 vs 2.2 ± 0.4, p < 0.05), a higher intensity of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) (mean ± SEM 184 ± 28 vs 92 ± 23 arbitrary units, p < 0.05), and an increased GFAP surface area (%) (mean ± SEM 21.2 ± 2.6 vs 10.7 ± 2.1, p < 0.01) in aSAH tissue. Microglia surface area was approximately 40% larger around vessels with microthrombosis than those without microthrombosis (estimated marginal means [95% CI]; 6.1 [5.4-6.9] vs 4.3 [3.6-5.0], p < 0.001). Our results show that the microglial and astrocyte surface areas increased after aSAH and that microthrombosis and microglia are interrelated.

Aneurysm Prevalence and Quality of Life During Screening in Relatives of Patients With Unruptured Intracranial Aneurysms: A Prospective Study.

BACKGROUND AND OBJECTIVES: Screening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives (FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening is also effective for FDRs of patients with UIA is unknown. We determined the yield of screening in such FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, identified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL). METHODS: In this prospective cohort study, we included FDRs, aged 20-70 years, of patients with UIA without a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 participating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magnetic resonance angiography between 2017 and 2021. We determined UIA prevalence and developed a prediction model for UIA risk at screening using multivariable logistic regression. QoL was evaluated with questionnaires 6 times during the first year after screening and assessed with a linear mixed-effects model. RESULTS: We detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI 3.2-7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2-4 mm), and the median 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%-0.9%). All UIAs received follow-up imaging, and none were treated preventively. After a median follow-up of 24 months (IQR 13-38 months), no UIA had changed. Predicted UIA risk at screening ranged between 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcohol consumption (c-statistic: 0.76; 95% CI 0.65-0.88). At all survey moments, health-related QoL and emotional functioning were comparable with those in a reference group from the general population. One FDR with a positive screening result expressed regret about screening. DISCUSSION: Based on the current data, we do not advise screening FDRs of patients with UIA because all identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. A longer follow-up should determine the risk of aneurysm growth requiring preventive treatment.

Clinically Established Temporomandibular Involvement in Adults With Juvenile Idiopathic Arthritis.

OBJECTIVE: To study clinical variables defining temporomandibular function in adults with juvenile idiopathic arthritis (JIA) and healthy controls. METHODS: In this cross-sectional study, the temporomandibular joint (TMJ) screening protocol, mandibular range of motion (MROM), and anterior maximum voluntary bite force (AMVBF) were compared between adults with JIA and healthy controls. Unadjusted and adjusted models with corrections for sex and disease duration were constructed for active maximum interincisal mouth opening (AMIO) and AMVBF. RESULTS: A total of 100 adults with JIA and 59 healthy adults were included in this study. In adults with JIA, 56% had clinically established TMJ involvement. AMIO was the MROM variable most reduced by TMJ involvement; AMIO was 8.8 mm (95% CI -11.40 to -6.12; P < 0.001) less in adults with JIA with TMJ involvement compared to JIA without TMJ involvement. No differences of AMIO were found between healthy adults and adults with JIA without TMJ involvement (-2.52, 95% CI -5.13 to 0.10; P = 0.06). Male sex was associated with a higher AMIO, and disease duration was associated with a decreased AMIO. Collinearity between the subtype prebiologic era and disease duration was found. AMVBF did not differ between adults with JIA and healthy adults. CONCLUSION: The high prevalence of clinically established TMJ involvement in adults with JIA indicates the need for awareness of TMJ problems in adults with JIA. TMJ involvement negatively influenced AMIO and should therefore be part of the TMJ screening in adults with JIA. AMVBF seems to have less utility for TMJ screening in adult populations.

Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity: a large pragmatic daily practice study from the BioDay registry.

BACKGROUND: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. OBJECTIVES: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. METHODS: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. RESULTS: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022. CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective.

The circadian clock remains intact, but with dampened hormonal output in heart failure.

BACKGROUND: Circadian (24-h) rhythms are important regulators in physiology and disease, but systemic disease may disrupt circadian rhythmicity. Heart failure (HF) is a systemic disease affecting hormonal regulation. We investigate whether HF affects the rhythmic expression of melatonin and cortisol, main endocrine products of the central clock, and cardiac-specific troponin in patients. We corroborate the functionality of the peripheral clock directly in the organs of translational models, inaccessible in human participants. METHODS: We included 46 HF patients (71.7% male, median age of 60 years, NYHA class II (32.6%) or III (67.4%), ischemic cardiomyopathy (43.5%), comorbidities: diabetes 21.7%, atrial fibrillation 30.4%), and 24 matched controls. Blood was collected at seven time-points during a 24-h period (totalling 320 HF and 167 control samples) for melatonin, cortisol, and cardiac troponin T (cTnT) measurements after which circadian rhythms were assessed through cosinor analyses, both on the individual and the group level. Next, we analysed peripheral circadian clock functionality using cosinor analysis in male animal HF models: nocturnal mice and diurnal zebrafish, based on expression of core clock genes in heart, kidneys, and liver, every 4 h during a 24-h period in a light/darkness synchronised environment. FINDINGS: Melatonin and cortisol concentrations followed a physiological 24-h pattern in both patients and controls. For melatonin, acrophase occurred during the night for both groups, with significantly decreased amplitude (median 5.2 vs 8.8, P = 0.0001) and circadian variation ([maximum]/[minimum]) in heart failure patients. For cortisol, mesor showed a significant increase for HF patients (mean 331.9 vs 275.1, P = 0.017) with a difference of 56.8 (95% CI 10.3-103.3) again resulting in a relatively lower variation: median 3.9 vs 6.3 (P = 0.0058). A nocturnal blood pressure dip was absent in 77.8% of HF patients. Clock gene expression profiles (Bmal, Clock, Per, Cry) were similar and with expected phase relations in animal HF models and controls, demonstrating preserved peripheral clock functionality in HF. Furthermore, oscillations in diurnal zebrafish were expectedly in opposite phases to those of nocturnal mice. Concordantly, cTnT concentrations in HF patients revealed significant circadian oscillations. INTERPRETATION: Central clock output is dampened in HF patients while the molecular peripheral clock, as confirmed in animal models, remains intact. This emphasises the importance of taking timing into account in research and therapy for HF, setting the stage for another dimension of diagnostic, prognostic and therapeutic approaches. FUNDING: Hartstichting.

Generalizability of the Results of Efficacy Trials in First-Episode Schizophrenia: Comparing Outcome and Study Discontinuation of Groups of Participants in the Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) Trial.

Objective: In the majority of randomized controlled trials (RCTs) conducted in schizophrenia populations, patients suffering from a substance use disorder (SUD) or suicidality are excluded. Excluding these patients from RCTs might impact the generalizability of results. The aim of this study is to determine whether excluding patients with suicidality and/or SUD impacts RCT results on symptomatic remission, premature study discontinuation, symptom severity, and social functioning.Methods: Across Europe and Israel, 481 patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder, based on DSM-IV criteria, were recruited between May 26, 2011, and May 15, 2016, for the Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) trial. Baseline characteristics and follow-up assessments were compared between patients with versus without baseline SUD and/or suicidality.Results: A total of 446 patients met eligibility criteria for the OPTiMiSE trial and initiated amisulpride treatment, of whom 404 (91%) had data available on suicidality, SUD, duration of illness, and CDS score. Of the 360 eligible patients with baseline data on suicidality and SUD, 106 patients had comorbid suicidality and/or SUD while 254 patients had neither of these comorbidities. No significant differences in the likelihood to achieve symptomatic remission or to prematurely discontinue the study were found when comparing comorbid versus non-comorbid patients (P = .27). There were no significant differences in symptom severity and social functioning between the groups. Comorbid patients had a higher level of depressive symptoms and more impaired social functioning compared to non-comorbid patients.Discussion: Excluding first-episode schizophrenia patients with comorbidities from clinical trials unlikely affects key outcome measures. It is recommended to include patients with comorbidities in clinical trials while carefully monitoring suicidality and implementing safety plans to gain insight into efficacy and safety of treatment in this substantial patient population.Trial Registration: ClinicalTrials.gov identifier: NCT01248195.

Effectiveness of analgesic ear drops as add-on treatment to oral analgesics in children with acute otitis media: study protocol of the OPTIMA pragmatic randomised controlled trial.

INTRODUCTION: Ear pain is the most prominent symptom of childhood acute otitis media (AOM). To control the pain and reduce reliance on antibiotics, evidence of effectiveness for alternative interventions is urgently needed. This trial aims to investigate whether analgesic ear drops added to usual care provide superior ear pain relief over usual care alone in children presenting to primary care with AOM. METHODS AND ANALYSIS: This is a pragmatic, two-arm, individually randomised, open, superiority trial with cost-effectiveness analysis and nested mixed-methods process evaluation in general practices in the Netherlands. We aim to recruit 300 children aged 1-6 years with a general practitioner (GP) diagnosis of AOM and ear pain. Children will be randomly allocated (ratio 1:1) to either (1) lidocaine hydrochloride 5 mg/g ear drops (Otalgan) one to two drops up to six times daily for a maximum of 7 days in addition to usual care (oral analgesics, with/without antibiotics); or (2) usual care. Parents will complete a symptom diary for 4 weeks as well as generic and disease-specific quality of life questionnaires at baseline and 4 weeks. The primary outcome is the parent-reported ear pain score (0-10) over the first 3 days. Secondary outcomes include proportion of children consuming antibiotics, oral analgesic use and overall symptom burden in the first 7 days; number of days with ear pain, number of GP reconsultations and subsequent antibiotic prescribing, adverse events, complications of AOM and cost-effectiveness during 4-week follow-up; generic and disease-specific quality of life at 4 weeks; parents' and GPs' views and experiences with treatment acceptability, usability and satisfaction. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee Utrecht, the Netherlands, has approved the protocol (21-447/G-D). All parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings. TRIAL REGISTRATION: The Netherlands Trial Register: NL9500; date of registration: 28 May 2021. At the time of publication of the study protocol paper, we were unable to make any amendments to the trial registration record in the Netherlands Trial Register. The addition of a data sharing plan was required to adhere to the International Committee of Medical Journal Editors guidelines. The trial was therefore reregistered in ClinicalTrials.gov (NCT05651633; date of registration: 15 December 2022). This second registration is for modification purposes only and the Netherlands Trial Register record (NL9500) should be regarded as the primary trial registration.

Home telemonitoring versus hospital care in complicated pregnancies in the Netherlands: a randomised, controlled non-inferiority trial (HoTeL).

BACKGROUND: Women with complicated pregnancies often require hospital admission. Telemonitoring at home is a promising alternative that fulfils a worldwide need in obstetric health care. Moreover, the COVID-19 pandemic has accelerated the transformation to digital care. The aim of this study was to evaluate safety, clinical effectiveness, patient satisfaction, and costs of home telemonitoring against hospital care in complicated pregnancies. METHODS: We did a multicentre, randomised, controlled, non-inferiority trial in six hospitals (four general teaching hospitals and two university hospitals) in the Netherlands (located in Utrecht, Amsterdam, and Groningen). Women aged 18 years and older with singleton pregnancies (>26 weeks gestation) requiring monitoring for pre-eclampsia, fetal growth restriction, fetal anomaly, preterm rupture of membranes, reduced fetal movements, or history of fetal death were included in the study. Participants were randomly assigned to either hospital admission or telemonitoring in (1:1), stratified for the six diagnoses for inclusion and the six centres of inclusion, using block randomisation (block sizes of four and six). When assigned to telemonitoring, participants went home with devices for cardiotocography and blood pressure measurements and had daily contact with their care providers after digitally sending their home measurements. When assigned to hospital admission, participants received care as usual on the ward until the postpartum period. The primary outcome was a composite of adverse perinatal outcomes assessed after delivery, including mortality; an Apgar score below 7 after 5 min or an umbilical arterial pH at birth below 7·05; maternal morbidity; admission of the newborn to the neonatal intensive care unit; and rate of caesarean section. The primary outcome was assessed in the intention-to-treat population. The non-inferiority margin for the primary outcome was a 10% absolute increase in composite primary endpoint based on baseline 20% incidence. The study was registered at the Dutch Trial Registration (NL5888) and is now closed to new participants. FINDINGS: From Dec 1, 2016, to Nov 30, 2019, 201 pregnant women were randomly assigned to an intervention procedure. 101 women were allocated to the telemonitoring group and 100 to the hospital admission group. One participant in the telemonitoring group withdrew consent before the intervention was initiated, and 100 participants were analysed for the primary outcome. In the hospital admission group, four participants did not receive the allocated intervention because they did not accept hospital admission. 100 participants in each group were analysed for the primary outcome according to the intention-to-treat principal. No participants were lost to follow-up. The primary outcome occurred in 31 (31%) of 100 participants in the telemonitoring group and in 40 (40%) of 100 participants in the hospital admission group. Adjusted for centre of inclusion, diagnosis, and nulliparity, the risk difference in primary outcome between both groups was 10·3% (95% CI -22·4 to 2·2) lower in the telemonitoring group, below the pre-defined non-inferiority margin of 10% absolute increase. A similar distribution for each of the individual components within the composite primary outcome was seen between groups. Five serious adverse events were reported: one neonatal death in the hospital admission group, in addition to one intra-uterine fetal death, two neonatal deaths, and one case of eclampsia in the telemonitoring group, all unrelated to the study. INTERPRETATION: This non-inferiority trial shows the first evidence that telemonitoring might be as safe as hospital admission for monitoring complicated pregnancies. FUNDING: Stichting Achmea Gezondheidszorg and ICT Healthcare Technology Solutions.

Effectiveness of Upadacitinib in Patients with Atopic Dermatitis including those with Inadequate Response to Dupilumab and/or Baricitinib: Results from the BioDay Registry.

Clinical trials showed that upadacitinib, a selective Janus kinase-1 inhibitor, is effective for treatment of moderate-to-severe atopic dermatitis. However, daily practice studies are limited. This multicentre prospective study evaluated the effectiveness of 16 weeks of upadacitinib treatment for moderate-to-severe atopic dermatitis in adult patients, including those with previous inadequate response to dupilumab and/or baricitinib, in daily practice. A total of 47 patients from the Dutch BioDay registry treated with upadacitinib were included. Patients were evaluated at baseline, and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed by clinician- and patient-reported outcome measurements. Safety was assessed by adverse events and laboratory assessments. Overall, the probabilities (95% confidence intervals) of achieving Eczema Area and Severity Index ≤ 7 and Numerical Rating Scale - pruritus ≤ 4 were 73.0% (53.7-86.3) and 69.4% (48.7-84.4), respectively. The effectiveness of upadacitinib was comparable in patients with inadequate response to dupilumab and/or baricitinib and in patients who were naïve for these treatments or who had stopped such treatments due to adverse events. Fourteen (29.8%) patients discontinued upadacitinib due to ineffectiveness, adverse events or both (8.5%, 14.9% and 6.4%, respectively). Most frequently reported adverse events were acneiform eruptions (n = 10, 21.3%), herpes simplex (n = 6, 12.8%), nausea and airway infections (both n = 4, 8.5%). In conclusion, upadacitinib is an effective treatment for patients with moderate-to-severe atopic dermatitis, including those with previous inadequate response to dupilumab and/or baricitinib treatment.

Reliability and measurement error of anterior maximum voluntary bite force in children with juvenile idiopathic arthritis and healthy children.

In children with juvenile idiopathic arthritis (JIA) the temporomandibular joint (TMJ) can be involved. As a consequence, the oral function can be impaired due to joint and/or muscle involvement of the masticatory system with a negative influence on the maximum bite force. The aim of this cross-sectional study was to establish the reliability of AMVBF in children with JIA and healthy children. Children with JIA and healthy children conducted three attempts of AMVBF. The reliability of AMVBF measurement was determined by the intra-class correlation coefficient (ICC) by age, standard error of measurement (SEM), smallest detectable change (SDC), and limits of agreement (LoA). A total of 298 children with JIA and 168 healthy children were examined. The AMVBF measurements showed an good to excellent reliability in children with JIA based on the ICCs corrected for age (0.782-0.979). In healthy children, the reliability was moderate to excellent (0.546-0.999). The SDC in our study indicated that values above 11.4N might be a clinical relevant change over time in children with JIA. The LoA showed a wide spread of variability in both children with JIA (-72.6-44.4N) and healthy children (-79.9-72.8N). The Bland-Altman plots indicated that the differences between the test and retest increased in value proportionally to the biteforce value.