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.

Effect of a multifaceted antibiotic stewardship intervention to improve antibiotic prescribing for suspected urinary tract infections in frail older adults (ImpresU): pragmatic cluster randomised controlled trial in four European countries.

OBJECTIVE: To evaluate whether antibiotic prescribing for suspected urinary tract infections in frail older adults can be reduced through a multifaceted antibiotic stewardship intervention. DESIGN: Pragmatic, parallel, cluster randomised controlled trial, with a five month baseline period and a seven month follow-up period. SETTING: 38 clusters consisting of one or more general practices (n=43) and older adult care organisations (n=43) in Poland, the Netherlands, Norway, and Sweden, from September 2019 to June 2021. PARTICIPANTS: 1041 frail older adults aged 70 or older (Poland 325, the Netherlands 233, Norway 276, Sweden 207), contributing 411 person years to the follow-up period. INTERVENTION: Healthcare professionals received a multifaceted antibiotic stewardship intervention consisting of a decision tool for appropriate antibiotic use, supported by a toolbox with educational materials. A participatory-action-research approach was used for implementation, with sessions for education, evaluation, and local tailoring of the intervention. The control group provided care as usual. MAIN OUTCOME MEASURES: The primary outcome was the number of antibiotic prescriptions for suspected urinary tract infections per person year. Secondary outcomes included the incidence of complications, all cause hospital referrals, all cause hospital admissions, all cause mortality within 21 days after suspected urinary tract infections, and all cause mortality. RESULTS: The numbers of antibiotic prescriptions for suspected urinary tract infections in the follow-up period were 54 prescriptions in 202 person years (0.27 per person year) in the intervention group and 121 prescriptions in 209 person years (0.58 per person year) in the usual care group. Participants in the intervention group had a lower rate of receiving an antibiotic prescription for a suspected urinary tract infection compared with participants in the usual care group, with a rate ratio of 0.42 (95% confidence interval 0.26 to 0.68). No differences between intervention and control group were observed in the incidence of complications (<0.01 v 0.05 per person year), hospital referrals (<0.01 v 0.05), admissions to hospital (0.01 v 0.05), and mortality (0 v 0.01) within 21 days after suspected urinary tract infections, nor in all cause mortality (0.26 v 0.26). CONCLUSIONS: Implementation of a multifaceted antibiotic stewardship intervention safely reduced antibiotic prescribing for suspected urinary tract infections in frail older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03970356.

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.

Carotid Artery Stenosis and Progression of Hemispheric Brain Atrophy: The SMART-MR Study.

INTRODUCTION: It has been hypothesized that carotid artery stenosis (CAS) may lead to greater atrophy of subserved brain regions; however, prospective studies on the impact of CAS on progression of hemispheric brain atrophy are lacking. We examined the association between CAS and progression of hemispheric brain atrophy. METHODS: We included 654 patients (57 ± 9 years) of the SMART-MR study, a prospective cohort study of patients with manifest arterial disease. Patients had baseline CAS duplex measurements and a 1.5T brain MRI at baseline and after 4 years of follow-up. Mean change in hemispheric brain volumes (% of intracranial volume [ICV]) was estimated between baseline and follow-up for left-sided and right-sided CAS across three degrees of stenosis (mild [≤29%], moderate [30-69%], and severe [≥70%]), adjusting for demographics, cerebrovascular risk factors, and brain infarcts. RESULTS: Mean decrease in left and right hemispheric brain volumes was 1.15% ICV and 0.82% ICV, respectively, over 4 years of follow-up. Severe right-sided CAS, compared to mild CAS, was associated with a greater decrease in volume of the left hemisphere (B = -0.49% ICV, 95% CI: -0.86 to -0.13) and more profoundly of the right hemisphere (B = -0.90% ICV, 95% CI: -1.27 to -0.54). This pattern was independent of cerebrovascular risk factors, brain infarcts, and white matter hyperintensities on MRI, and was also observed when accounting for the presence of severe bilateral CAS. Increasing degrees of left-sided CAS, however, was not associated with greater volume loss of the left or right hemisphere. CONCLUSIONS: Our data indicate that severe (≥70%) CAS could represent a risk factor for greater ipsilateral brain volume loss, independent of cerebrovascular risk factors, brain infarcts, or white matter hyperintensities on MRI. Further longitudinal studies in other cohorts are warranted to confirm this novel finding.

Dupilumab in daily practice for the treatment of pediatric atopic dermatitis: 28-week clinical and biomarker results from the BioDay registry.

BACKGROUND: Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice studies are available. The aim of this study is to evaluate the effect of 28 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice. METHODS: Patients visited the outpatient clinic at baseline, 4, 16, and 28 weeks of treatment. Disease severity was assessed by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS)-pruritus and -pain, and the Patient-Oriented Eczema Measure (POEM). Side effects were evaluated. Nineteen severity-associated serum biomarkers were measured. Predicted-EASI (p-EASI) was calculated. RESULTS: Sixty-one patients were included. Respectively 75.4%, 49.2%, and 24.6% reached EASI-50, EASI-75, and EASI-90 and 36.1% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain was reached by 84.7%, 45.3%, and 77.4%, respectively. Most reported side effects were conjunctivitis (n = 10) and headache (n = 4). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significant correlation with disease severity. CONCLUSION: Dupilumab treatment significantly improved disease severity and disease-associated symptoms and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice.

Association of Serum Dupilumab Levels at 16 Weeks With Treatment Response and Adverse Effects in Patients With Atopic Dermatitis: A Prospective Clinical Cohort Study From the BioDay Registry.

Importance: The registered dose of dupilumab for adult patients with atopic dermatitis (AD) is 300 mg every other week. At present, it is unknown whether serum dupilumab levels are associated with treatment response or adverse effects. Objectives: To evaluate serum dupilumab levels at 16 weeks of treatment and to explore the association of serum dupilumab levels with treatment response and adverse effects in patients with AD. Design, Setting, and Participants: This clinical, prospective, observational cohort study used data from the prospective BioDay Registry including adult patients with AD who started dupilumab treatment and for whom a serum sample was available at 16 weeks of treatment. All patients were treated according to the BioDay protocol in the University Medical Center Utrecht in the Netherlands. Patients received a loading dose of dupilumab 600 mg subcutaneously, followed by 300 mg every other week. Patients who had a dose adjustment or discontinued treatment before 16 weeks of treatment were excluded. Data analyses were performed from January to June 2022. Main Outcomes and Measures: Disease severity of AD was assessed at baseline and at weeks 16 and 52 using the Eczema Area and Severity Index (EASI). Treatment response was defined as the percent reduction in EASI score vs the baseline score (eg, EASI 90 indicated a 90% reduction) and as an absolute EASI cutoff score of 7 or lower (controlled AD). Adverse effects were recorded during the first year. At 16 weeks, dupilumab serum levels and treatment responses were measured and analyzed. Multivariate logistic regression modeling was used to determine the prediction of response (EASI 90; EASI ≤7) and adverse effects at 52 weeks, with serum dupilumab levels at 16 weeks in the presence of the covariates age and sex. Results: Among the total of 295 patients with AD (mean [SD] age, 41.5 [15.9] years; 170 [57.6%] men), the median (IQR [range]) drug level was 86.6 µg/mL (64.6-110.0 µg/mL [10.1-382.0 µg/mL]) at 16 weeks of treatment. No significant differences were found in serum dupilumab levels between responder statuses (EASI, <50, 50, 75, or 90) at week 16. Multivariate logistic regression analysis showed nonsignificant odds ratios (ORs) for serum dupilumab levels at 16 weeks regarding prediction of long-term response (EASI ≥90: OR, 0.96 [95% CI, 0.90-1.04; P = .34] and EASI ≤7: OR, 1.03 [95% CI, 0.93-1.14; P = .55]) and adverse effects (OR, 1.01 [95% CI, 0.95-1.07; P = .83]). Conclusion and Relevance: This prospective clinical cohort study found a broad range of serum dupilumab levels at 16 weeks of treatment and no association with treatment response and adverse effects during first year of treatment. Response may be dependent on target availability of the interleukin-4 receptor subunit α, with an interpatient variability producing heterogeneity in response.

Daily Practice Experience of Baricitinib Treatment for Patients with Difficult-to-Treat Atopic Dermatitis: Results from the BioDay Registry.

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.