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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

Background Hemodynamic stress is linked to the development of intracranial aneurysms (IAs) and may be influenced by anatomic variation of intracranial arteries. We assessed diameters and bifurcation angles of intracranial arteries forming the circle of Willis in a cohort of individuals screened for the presence of IAs. Methods Individuals with and without IAs identified at screening with magnetic resonance angiography were compared. Diameters and bifurcation angles of the following arteries were measured using semiautomatic methods: A1 and A2 segments of the anterior cerebral artery, M1 and M2 segments of the middle cerebral artery, P1 segments of the posterior cerebral artery, posterior communicating artery (Pcom), internal carotid artery, vertebral artery, and basilar artery. We employed univariate general linear models to assess group differences. This included subgroup comparisons between individuals with IAs at specific locations and matched controls, and comparisons on group level between individuals with and without IAs, corrected for age and sex. Results In 94 of the 1049 individuals (9.0%) included, IAs were detected. Individuals with middle cerebral artery IAs had wider ipsilateral M2–M2 bifurcation angles compared with controls (121±25° versus 97±19°; P

Summary: 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.

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.

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.

AimTo 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.MethodsFifteen 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.ResultsAmong 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.ConclusionsSalivary 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.

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.

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.

Abstract Background Recognition of temporomandibular joint (TMJ) involvement in children with juvenile idiopathic arthritis (JIA) has gained increasing attention in the past decade. The clinical assessment of mandibular range of motion characteristics is part of the recommended variables to detect TMJ involvement in children with JIA. The aim of this study was to explore explanatory variables for mandibular range of motion outcomes in children with JIA, with and without clinically established TMJ involvement, and in healthy children. Methods This cross-sectional study included children with JIA and healthy children of age 6–18 years. Mandibular range of motion variables included active and passive maximum interincisal opening (AMIO and PMIO), protrusion, laterotrusion, dental midline shift in AMIO and in protrusion. Additionally, the TMJ screening protocol and palpation pain were assessed. Adjusted linear regression analyses of AMIO, PMIO, protrusion, and laterotrusion were performed to evaluate the explanatory factors. Two adjusted models were constructed: model 1 to compare children with JIA and healthy children, and model 2 to compare children with JIA with and without TMJ involvement. Results A total of 298 children with JIA and 169 healthy children were included. Length was an explanatory variable for the mandibular range of motion excursions. Each centimeter increase in length increased AMIO (0.14 mm), PMIO (0.14 mm), and protrusion (0.02 mm). Male gender increased AMIO by 1.35 mm. Having JIA negatively influenced AMIO (3.57 mm), PMIO (3.71 mm), and protrusion (1.03 mm) compared with healthy children, while the discrepancy between left and right laterotrusion raised 0.68 mm. Children with JIA and TMJ involvement had a 8.27 mm lower AMIO, 7.68 mm lower PMIO and 0.96 mm higher discrepancy in left and right laterotrusion compared to healthy children. Conclusion All mandibular range of motion items were restricted in children with JIA compared with healthy children. In children with JIA and TMJ involvement, AMIO, PMIO and the discrepancy between left and right laterotrusion were impaired more severely. The limitation in protrusion and laterotrusion was hardly clinically relevant. Overall, AMIO is the mandibular range of motion variable with the highest restriction (in millimeters) in children with JIA and clinically established TMJ involvement compared to healthy children.

Abstract Background Treatment options for advanced head and neck adenoid cystic carcinoma (AdCC) are limited. Prostate-Specific Membrane Antigen (PSMA), a transmembrane protein that is known for its use in diagnostics and targeted therapy in prostate cancer, is also expressed by AdCC. This study aimed to analyse PSMA expression in a large cohort of primary, recurrent and metastasized AdCC of the head and neck. Methods One hundred ten consecutive patients with histologically confirmed AdCC in the period 1990–2017 were included. An analysis was made of clinical details, revised pathology and semiquantitative immunohistochemical expression of PSMA on tissue microarray and whole slides. Associations of PSMA expression with clinicopathological parameters were explored and survival was analysed by multivariate Cox-proportional Hazard analysis. Results PSMA expression was present in 94% of the 110 primary tumours, with a median of 31% positive cells (IQR 15–60%). Primary tumours (n = 18) that recurred (n = 15) and/or had metastases (n = 10) demonstrated 40, 60 and 23% expression respectively. Expression was not independently related to increased pathological stage, tumour grade, and the occurrence of locoregional recurrence or metastasis. After dichotomization, only primary tumour PSMA expression ≤10% appeared to be associated with reduced 10-years recurrence-free survival (HR 3.0, 95% CI 1.1–8.5, p = .04). Conclusions PSMA is highly expressed in primary, recurrent and metastatic AdCC of the salivary and seromucous glands. PSMA expression has no value in predicting clinical behaviour of AdCC although low expression may indicate a reduced recurrence-free survival. This study provides supporting results to consider using PSMA as target for imaging and therapy when other diagnostic and palliative treatment options fail.

Abstract Background The majority of the world’s perinatal deaths occur in low- and middle-income countries. A substantial proportion occurs intrapartum and is avoidable with better care. At a low-resource tertiary hospital, this study assessed the quality of intrapartum care and adherence to locally-tailored clinical guidelines. Methods A non-participatory, structured, direct observation study was held at Mnazi Mmoja Hospital, Zanzibar, Tanzania, between October and November 2016. Women in active labour were followed and structure, processes of labour care and outcomes of care systematically recorded. Descriptive analyses were performed on the labour observations and compared to local guidelines and supplemented by qualitative findings. A Poisson regression analysis assessed factors affecting foetal heart rate monitoring (FHRM) guidelines adherence. Results 161 labouring women were observed. The nurse/midwife-to-labouring-women ratio of 1:4, resulted in doctors providing a significant part of intrapartum monitoring. Care during labour and two-thirds of deliveries was provided in a one-room labour ward with shared beds. Screening for privacy and communication of examination findings were done in 50 and 34%, respectively. For the majority, there was delayed recognition of labour progress and insufficient support in second stage of labour. While FHRM was generally performed suboptimally with a median interval of 105 (interquartile range 57–160) minutes, occurrence of an intrapartum risk event (non-reassuring FHR, oxytocin use or poor progress) increased assessment frequency significantly (rate ratio 1.32 (CI 1.09–1.58)). Conclusions Neither international nor locally-adapted standards of intrapartum routine care were optimally achieved. This was most likely due to a grossly inadequate capacity of birth attendants; without whom innovative interventions at birth are unlikely to succeed. This calls for international and local stakeholders to address the root causes of unsafe intrafacility care in low-resource settings, including the number of skilled birth attendants required for safe and respectful births.

This study identified risk factors for the development of dupilumab-associated ocular surface disease in patients with moderate-to-severe atopic dermatitis in a large prospective daily practice cohort. Data from the Dutch BioDay Registry were used to assess the risk of developing dupilumab-associated ocular surface disease, by performing univariate and multivariate logistic regression analyses. A total of 469 patients were included, of which 152/469 (32.4%) developed dupilumab-associated ocular surface disease. Multivariate analysis showed a statistically significant association of the development of dupilumab-associated ocular surface disease with a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at the start of dupilumab (odds ratio 5.16, 95% confidence interval 2.30–11.56, p

Background The long‐term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. Methods and Results Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16–74 years]) were included. After a mean follow‐up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000–1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005–1.013 [P

Introduction Almost 60% of antibiotics in frail elderly are prescribed for alleged urinary tract infections (UTIs). A substantial part of this comprises prescriptions in case of non-specific symptoms or asymptomatic bacteriuria, for which the latest guidelines promote restrictiveness with antibiotics. We aim to reduce inappropriate antibiotic use for UTIs through an antibiotic stewardship intervention (ASI) that encourages to prescribe according to these guidelines. To develop an effective ASI, we first need a better understanding of the complex decision-making process concerning suspected UTIs in frail elderly. Moreover, the implementation approach requires tailoring to the heterogeneous elderly care setting.Methods and analysis First, we conduct a qualitative study to explore factors contributing to antibiotic prescribing for UTIs in frail elderly, using semi-structured interviews with general practitioners, nursing staff, patients and informal caregivers. Next, we perform a pragmatic cluster randomised controlled trial in elderly care organisations. A multifaceted ASI is implemented in the intervention group; the control group receives care as usual. The ASI is centred around a decision tool that promotes restrictive antibiotic use, supported by a toolbox with educational materials. For the implementation, we use a modified participatory-action-research approach, guided by the results of the qualitative study. The primary outcome is the number of antibiotic prescriptions for suspected UTIs. We aim to recruit 34 clusters with in total 680 frail elderly residents ≥70 years. Data collection takes place during a 5-month baseline period and a 7-month follow-up period. Finally, we perform a process evaluation. The study has been delayed for 6 months due to COVID-19 and is expected to end in July 2021.Ethics and dissemination Ethical approvals and/or waivers were obtained from the ethical committees in Poland, the Netherlands, Norway and Sweden. The results will be disseminated through publication in peer-reviewed journals and conference presentations.Trial registration number NCT03970356.

Background: Vitamin tests are increasingly ordered by GPs, but a clinical and evidence-based indication is often lacking. Harnessing technology (that is, decision support tools and redesigning request forms) have been shown to reduce vitamin requests. Aim: To investigate whether the number of vitamin tests may be reduced by providing a multi-level intervention programme based on training, monitoring, and feedback. Design & setting: This was a cluster randomised intervention study performed in 26 primary care health centres (>195 000 patients) in the Netherlands. The relative reduction in ordered vitamin D and B12 tests was determined after introduction of two de-implementation strategies (1 May 2017 to 30 April 2018). Method: Health centres randomised to de-implementation strategy 1 received education and benchmarking of their own vitamin test ordering behaviour every 3 months. Health centres in de-implementation strategy 2 received the same education and benchmarking, but supplemented with educational material for patients. Results: The number of vitamin D tests decreased by 23% compared to the 1-year pre-intervention period (1 May 2016 to 30 April 2017). For vitamin B12 tests an overall reduction of 20% was found. Provision of patient educational information showed additional value over training and benchmarking of GPs alone for vitamin D test ordering (10% extra reduction, odds ratio [OR] 0.88, 95% confidence interval [CI] = 0.83 to 0.92), but not for vitamin B12 ordering (4% extra reduction, OR 0.96, 95% CI = 0.91 to 1.02). Nationwide, this would result in over €3 200 000 in savings on healthcare expenditure a year. Conclusion: A structured intervention programme, including training and benchmarking of GPs regarding their diagnostic test ordering, resulted in a significant reduction in ordered vitamin tests. Additional information provision to patients resulted in a small but still relevant additional reduction. If implemented on a national level, a substantial cost saving could be achieved.

Background: MHealth interventions promise to bridge gaps in clinical care but documentation of their effectiveness is limited. We evaluated the utilization and effect of an mhealth clinical decision-making support intervention that aimed to improve neonatal mortality in Ghana by providing access to emergency neonatal protocols for frontline health workers. Methods: In the Eastern Region of Ghana, sixteen districts were randomized into two study arms (8 intervention and 8 control clusters) in a cluster-randomized controlled trial. Institutional neonatal mortality data were extracted from the District Health Information System-2 during an 18-month intervention period. We performed an intention-to-treat analysis and estimated the effect of the intervention on institutional neonatal mortality (primary outcome measure) using grouped binomial logistic regression with a random intercept per cluster. This trial is registered at ClinicalTrials.gov (NCT02468310) and Pan African Clinical Trials Registry (PACTR20151200109073). Findings: There were 65,831 institutional deliveries and 348 institutional neonatal deaths during the study period. Overall, 47∙3% of deliveries and 56∙9% of neonatal deaths occurred in the intervention arm. During the intervention period, neonatal deaths increased from 4∙5 to 6∙4 deaths and, from 3∙9 to 4∙3 deaths per 1000 deliveries in the intervention arm and control arm respectively. The odds of neonatal death was 2⋅09 (95% CI (1∙00;4∙38); p = 0∙051) times higher in the intervention arm compared to the control arm (adjusted odds ratio). The correlation between the number of protocol requests and the number of deliveries per intervention cluster was 0∙71 (p = 0∙05). Interpretation: The higher risk of institutional neonatal death observed in intervention clusters may be due to problems with birth and death registration, unmeasured and unadjusted confounding, and unintended use of the intervention. The findings underpin the need for careful and rigorous evaluation of mHealth intervention implementation and effects. Funding: Netherlands Foundation for Scientific Research - WOTRO, Science for Global Development; Utrecht University. Keywords: Neonatal mortality, Ghana, mHealth, Low and middle income countries

Objective: Military servicemen deployed to war zones are at increased risk of developing posttraumatic stress disorder (PTSD) and successful adaptation to stress is important. Epigenetic alterations in response to trauma have been identified as mechanism of adaptation and may therefore predict deployment-related PTSD symptoms. To date, human studies of epigenetic marks for traumatic stress have been largely constrained by short-term analyses of one or two time points. Method: This study in a prospective Dutch military cohort (N ​= ​125) examined longitudinal changes of DNA methylation profiles before, as well as one and six months after deployment-related combat exposure in relation to the development of PTSD symptoms over a period of up to five years after deployment. We investigated the predictive value of specific methylation changes for immediate and delayed-onset PTSD symptoms and recovery. This epigenetic prediction was compared to polygenic risk score predictions obtained from the currently available largest genome-wide association study of PTSD. Results: A total of fourteen genomic regions were identified in which PTSD symptom levels were associated with methylation changes over time (pre-deployment, one, and six months post-deployment). Of these regions, four were significant determinants of longitudinal development of PTSD symptoms. In addition, we observed that, together with risk level during deployment (operating inside or outside the military base) and physical childhood trauma, post-deployment decreases in methylation at a genomic region in EP300/miRNA1281 was associated with a delayed onset of PTSD compared to a resilient profile. Polygenic risk, in contrast, was related to PTSD onset within six months after deployment but was not associated with long term outcomes. Conclusion: The present study suggests predictive utility of changes in DNA methylation for the subsequent development of PTSD symptoms and showed that the currently available measure of polygenic risk is primarily related to non-delayed disease onset.

Background: Diagnosing heart failure (HF) is difficult, relying on medical history, symptoms, and signs only. Clinical guidelines recommend natriuretic peptides (NPs) as an additional diagnostic test, notably to exclude HF in suspected patients. NP testing has been available since 2003 for primary care in the Netherlands, but little is known about its uptake. Aim: To evaluate the trend in ordering and appropriateness of NP testing in primary care. Design & setting: An observational study was performed between January 2005 and December 2013. Nine Dutch general practices participated, with 21 000 registered people (approximately 4300 aged ≥65 years). Method: The total number of patients undergoing NP testing each year was calculated per 1000 patient years (PY) based on the total practice population. NP levels were used to assess whether NP testing was applied to exclude or confirm HF. Results: The number of NP testing increased from 2.5 per 1000 PY in 2005 to 14.0 per 1000 PY in 2013, with a peak in 2009 of 15.6 per 1000 PY. The proportion of participants with N-terminal B-type natriuretic peptide (NTproBNP) below 125 pg/ml (the exclusionary threshold recommended by the European Society of Cardiology [ESC] guidelines on HF) was on average 30%, and highest in the first year (47%). Conclusion: After a rapid uptake of NP testing in primary care from 2005 onwards, the use of it seemed to stabilise after 2009, thus leaving patients who are prone to HF without an optimal diagnostic work-up.

BackgroundPatients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3-6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care.Methods and findingsIn a randomized controlled trial, the decision to prolong or stop anticoagulant treatment was guided by predicted recurrence risk using the VPM (n = 441), which was compared with usual care (n = 442). Patients with unprovoked VTE were recruited from local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015, with 24-month follow-up complete for all patients by early 2018. The primary outcome was recurrent VTE during 24 months of follow-up. Secondary outcomes included major bleeding and clinically relevant non-major (CRNM) bleeding. In the total study population of 883 patients, mean age was 55 years, and 507 (57.4%) were men. A total of 96 recurrent VTE events (10.9%) were observed, 46 in the intervention arm and 50 in the control arm (risk ratio 0.92, 95% CI 0.63-1.35, p = 0.67). Major bleeding occurred in 4 patients, 2 in each treatment arm, whereas CRNM bleeding occurred in 20 patients (12 in intervention arm versus 8 in control arm). The VPM showed good discriminative power (c-statistic 0.76, 95% CI 0.69-0.83) and moderate to good calibration, notably at the lower spectrum of predicted risk. For instance, in 284 patients with a predicted risk of >2% to 4%, the observed rate of recurrence was 2.5% (95% CI 0.7% to 4.3%). The main limitation of this study is that it did not enroll the preplanned number of 750 patients in each study arm due to declining recruitment rate.ConclusionsOur results show that application of the VPM in all patients with unprovoked VTE is unlikely to reduce overall recurrence risk. Yet, in those with a low predicted risk of recurrence, the observed rate was also low, suggesting that it might be safe to stop anticoagulant treatment in these patients.Trial registrationNetherlands Trial Register NTR2680.

Abstract Background HIV infection and antiretroviral treatment are associated with changes in lipid levels, insulin resistance and risk of cardiovascular disease (CVD). We investigated these changes in the first 96 weeks of treatment with low-dose stavudine or tenofovir regimens. Methods This is a secondary analysis of a double blind, randomised controlled trial performed in South-Africa, Uganda and India comparing low-dose stavudine (20 mg twice daily) with tenofovir in combination with efavirenz and lamivudine in antiretroviral-naïve adults (n = 1067) (Clinicaltrials.gov, NCT02670772). Over 96 weeks, data were collected on fasting lipids, glucose and insulin. Insulin resistance was assessed with the HOMA-IR index and 10-year CVD risk with the Framingham risk score (FRS). A generalized linear mixed model was used to estimate trends over time. Results Participants were on average 35.3 years old, 57.6% female and 91.8% Black African. All lipid levels increased following treatment initiation, with the sharpest increase in the first 24 weeks of treatment. The increase in all lipid subcomponents over 96 weeks was higher among those in the stavudine than the tenofovir group. Insulin resistance increased steadily with no difference detected between study groups. FRS rose from 1.90% (1.84–1.98%) at baseline to 2.06 (1.98–2.15%) at week 96 for the total group, with no difference between treatment arms (p = 0.144). Lipid changes were more marked in Indian than African participants. Conclusion Lipid levels increased in both groups, with low-dose stavudine resulting in a worse lipid profile compared to tenofovir. Insulin resistance increased, with no difference between regimens. CVD risk increased over time and tended to increase more in the group on stavudine. The low CVD risk across both arms argues against routine lipid and glucose monitoring in the absence of other CVD risk factors. In high risk patients, monitoring may only be appropriate at least a year after treatment initiation.

Abstract Background Health care providers aim to stimulate self-management in type 2 diabetes (T2DM) patients. However, they have a limited number of patient contacts to do this. With the growing number of T2DM patients, innovative and cost-effective interventions to promote self-management are needed. We aim to evaluate the effectiveness of diabetes self-management education via a smartphone app in T2DM patients on insulin therapy. Methods Non-blinded two-arm multi-centre randomised controlled superiority trial with parallel-groups and equal randomisation (‘TRIGGER study’). Eligible patients are 40–70 years, on insulin therapy since at least 3 months, with HbA1c > 53 mmol/mol (> 7%). In total 228 patients will be recruited. The intervention group (n = 114) will receive diabetes self-management education via a smartphone app to trigger diabetes self-management: unidirectional text messages, free of charge, evidence and psychological theory based, with regard to dietary habits, physical activity, hypoglycaemia and glucose variability. Patients choose their preferred frequency (two to six times per week), topics (two or three additionally to hypoglycaemia, which is an obligatory topic), and duration (6 or 9 months). The control group (n = 114) will receive care-as-usual. The primary study endpoint is the HbA1c level after a follow-up of 6 months. The percentage of patients who achieve an HbA1c level ≤ 53 mmol/mol (≤7%) without hypoglycaemia (plasma glucose

BackgroundPostpartum hemorrhage (PPH) is the leading cause of direct maternal mortality globally and in Suriname. We aimed to study the prevalence, risk indicators, causes, and management of PPH to identify opportunities for PPH reduction.MethodsA nationwide retrospective descriptive study of all hospital deliveries in Suriname in 2017 was performed. Logistic regression analysis was applied to identify risk indicators for PPH (≥ 500ml blood loss). Management of severe PPH (blood loss ≥1,000ml or ≥500ml with hypotension or at least three transfusions) was evaluated via a criteria-based audit using the national guideline.ResultsIn 2017, the prevalence of PPH and severe PPH in Suriname was 9.2% (n = 808/8,747) and 2.5% (n = 220/8,747), respectively. PPH varied from 5.8% to 15.8% across the hospitals. Risk indicators associated with severe PPH included being of African descent (Maroon aOR 2.1[95%CI 1.3-3.3], Creole aOR 1.8[95%CI 1.1-3.0]), multiple pregnancy (aOR 3.4[95%CI 1.7-7.1]), delivery in Hospital D (aOR 2.4[95%CI 1.7-3.4]), cesarean section (aOR 3.9[95%CI 2.9-5.3]), stillbirth (aOR 6.4 [95%CI 3.4-12.2]), preterm birth (aOR 2.1[95%CI 1.3-3.2]), and macrosomia (aOR 2.8 [95%CI 1.5-5.0]). Uterine atony (56.7%, n = 102/180[missing 40]) and retained placenta (19.4%, n = 35/180[missing 40]), were the main causes of severe PPH. A criteria-based audit revealed that women with severe PPH received prophylactic oxytocin in 61.3% (n = 95/155[missing 65]), oxytocin treatment in 68.8% (n = 106/154[missing 66]), and tranexamic acid in 4.9% (n = 5/103[missing 117]).ConclusionsPPH prevalence and risk indicators in Suriname were similar to international and regional reports. Inconsistent blood loss measurement, varied maternal and perinatal characteristics, and variable guideline adherence contributed to interhospital prevalence variation. PPH reduction in Suriname can be achieved through prevention by practicing active management of the third stage of labor in every birth and considering risk factors, early recognition by objective and consistent blood loss measurement, and prompt treatment by adequate administration of oxytocin and tranexamic acid according to national guidelines.

Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA.

Mark J Valk,1 Berna D Broekhuizen,1 Arend Mosterd,1,2 Nicolaas P Zuithoff,1 Arno W Hoes,1 Frans H Rutten1 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 2Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands Background: Presence of chronic obstructive pulmonary disease (COPD) in heart failure (HF) has prognostic and therapeutic implications. Exact prevalence estimates are lacking because most previous studies estimated the prevalence of COPD among HF patients while unstable and in the presence of pulmonary congestion.Methods: Community-dwelling patients with an established diagnosis of HF and in a stable phase of their disease were invited for spirometry. COPD was defined according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification and considered present if the ratio of the post-bronchodilator forced expiratory volume in 1 second and forced vital capacity was below 0.7.Results: Thirty of the 106 patients with HF (mean age 76 [standard deviation] 11.9 years, 57% male) had COPD (prevalence 28.3% [95% confidence interval (CI) 19.7%–36.9%]), with similar rates among those with HF and a reduced ejection fraction (18 individuals; prevalence 28.6% [95% CI 20.0%–37.2%]) and HF with preserved ejection fraction (12 individuals; prevalence 27.9% [95% CI 19.4–36.4]). Twenty-one (70%) of the 30 participants were newly detected cases of COPD.Conclusion: More than a quarter of the patients with HF concomitantly have COPD, with the large majority being previously unrecognized. Coexistence of COPD should be considered more often in these patients. Keywords: heart failure, COPD, prevalence, comorbidity, spirometry, diagnosis, primary care

BackgroundWe investigated the reporting and methods of prediction studies, focusing on aims, designs, participant selection, outcomes, predictors, statistical power, statistical methods, and predictive performance measures.Methods and findingsWe used a full hand search to identify all prediction studies published in 2008 in six high impact general medical journals. We developed a comprehensive item list to systematically score conduct and reporting of the studies, based on recent recommendations for prediction research. Two reviewers independently scored the studies. We retrieved 71 papers for full text review: 51 were predictor finding studies, 14 were prediction model development studies, three addressed an external validation of a previously developed model, and three reported on a model's impact on participant outcome. Study design was unclear in 15% of studies, and a prospective cohort was used in most studies (60%). Descriptions of the participants and definitions of predictor and outcome were generally good. Despite many recommendations against doing so, continuous predictors were often dichotomized (32% of studies). The number of events per predictor as a measure of statistical power could not be determined in 67% of the studies; of the remainder, 53% had fewer than the commonly recommended value of ten events per predictor. Methods for a priori selection of candidate predictors were described in most studies (68%). A substantial number of studies relied on a p-value cut-off of pConclusionsThe majority of prediction studies in high impact journals do not follow current methodological recommendations, limiting their reliability and applicability.

BACKGROUND:The first antenatal clinic (ANC) visit helps to distinguish pregnant women who require standard care, from those with specific problems and so require special attention. There are protocols to guide care providers to provide optimal care to women during ANC. Our objectives were to determine the level of provider adherence to first antenatal visit guidelines in the Safe Motherhood Protocol (SMP), and assess patient factors that determine complete provider adherence. METHODS:This cross-sectional study is part of a cohort study that recruited women who delivered in eleven health facilities and who had utilized antenatal care services during their pregnancy in the Greater Accra region of Ghana. A record review of the first antenatal visit of participants was carried out to assess the level of adherence to the SMP, using a thirteen-point checklist. Information on their socio-demographic characteristics and previous pregnancy history was collected using a questionnaire. Percentages of adherence levels and baseline characteristics were estimated and cluster-adjusted odds ratios (OR) calculated to identify determinants. RESULTS:A total of 948 women who had delivered in eleven public facilities were recruited with a mean age (SD) of 28.2 (5.4) years. Overall, complete adherence to guidelines pertained to only 48.1% of pregnant women. Providers were significantly more likely to completely adhere to guidelines when caring for multiparous women [OR = 5.43 (1.69-17.44), p

Despite the availability of high-sensitive troponin (hs-cTnT), there is still room for improvement in the diagnostic assessment of patients suspected of acute coronary syndrome (ACS). Apart from serial biomarker testing, which is time-consuming, novel biomarkers like copeptin have been proposed to expedite the early diagnosis of suspected ACS in addition to hs-cTnT. We determined whether placenta derived growth factor (PlGF), soluble Fms-like tyrosine kinase 1 (sFlt-1), myoglobin, N-terminal prohormone B-type Natriuretic Peptide (NT-proBNP), growth-differentiation factor 15 (GDF-15) and copeptin improved early assessment of chest pain patients.This prospective, single centre diagnostic FAME-ER study included patients presenting to the ED with symptoms suggestive of ACS. Blood was collected to measure biomarkers, notably, hs-cTnT was retrospectively assessed. Added value of markers was judged by increase in AUC using multivariable logistic regression.Of 453 patients enrolled, 149 (33%) received a final diagnosis of ACS. Hs-cTnT had the highest diagnostic value in both univariable and multivariable analysis. PPVs of the biomarkers ranged from 23.5% (PlGF) to 77.9% (hs-cTnT), NPVs from 67.0% (PlGF) to 86.4% (hs-cTnT). Only myoglobin yielded diagnostic value in addition to clinical symptoms and electrocardiography (ECG) (AUC of clinical model 0.80) with AUC of 0.84 (p

BACKGROUND: The interest in prognostic reviews is increasing, but to properly review existing evidence an accurate search filer for finding prediction research is needed. The aim of this paper was to validate and update two previously introduced search filters for finding prediction research in Medline: the Ingui filter and the Haynes Broad filter. METHODOLOGY/PRINCIPAL FINDINGS: Based on a hand search of 6 general journals in 2008 we constructed two sets of papers. Set 1 consisted of prediction research papers (n = 71), and set 2 consisted of the remaining papers (n = 1133). Both search filters were validated in two ways, using diagnostic accuracy measures as performance measures. First, we compared studies in set 1 (reference) with studies retrieved by the search strategies as applied in Medline. Second, we compared studies from 4 published systematic reviews (reference) with studies retrieved by the search filter as applied in Medline. Next--using word frequency methods--we constructed an additional search string for finding prediction research. Both search filters were good in identifying clinical prediction models: sensitivity ranged from 0.94 to 1.0 using our hand search as reference, and 0.78 to 0.89 using the systematic reviews as reference. This latter performance measure even increased to around 0.95 (range 0.90 to 0.97) when either search filter was combined with the additional string that we developed. Retrieval rate of explorative prediction research was poor, both using our hand search or our systematic review as reference, and even combined with our additional search string: sensitivity ranged from 0.44 to 0.85. CONCLUSIONS/SIGNIFICANCE: Explorative prediction research is difficult to find in Medline, using any of the currently available search filters. Yet, application of either the Ingui filter or the Haynes broad filter results in a very low number missed clinical prediction model studies.

• Home telemonitoring may partly substitute face-to-face contacts in stable outpatients with heart failure. • Stable heart failure patients receiving a non-invasive e-health adjusted care pathway had similar reduction in NT-proBNP values than those receiving usual care with on average four face-to-face contacts a year. • More studies are needed to evaluate substitution of face-to-face contacts by e-health. Home telemonitoring in heart failure (HF) patients may reduce workload of HF nurses by reducing face-to-face contacts. The aim of this study is to assess whether telemonitoring as a substitution could have negative effects as expressed by less reduction in circulating natriuretic peptide levels between baseline and one-year of follow up compared to usual care. A post-hoc analysis of the e-Vita HF trial, a three-arm parallel randomized trial conducted in stable HF patients. Patients were randomized into three arms: (i) usual HF outpatient care, (ii) usual care combined with the use of the website heartfailurematters.org, and (iii) telemonitoring (e-Vita HF platform) instead of face-to-face consultations. Mixed linear model analyses were applied to assess differences in the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels between the three arms over a year. A total of 223 participants could be included (mean age 67.1 ± 10.1 years, 27% women, New York Heart Association class I–IV; 39%, 38%, 14%, and 9%). The mean left ventricular ejection fraction was 35 ± 10%. The median of routine face-to-face contacts over a year was 1.0 lower (2.0 vs. 3.0) in the third arm compared with usual care. Median NT-proBNP levels did not significantly differ between the three arms. In stable and optimally treated HF patients, telemonitoring causing a reduction of routine face-to-face contacts seems not to negatively affect hemodynamic status as measured by NT-proBNP levels over time. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background There is a need for brief instruments to ascertain the diagnosis of major depressive disorder. In this study, we present the reliability, construct validity and accuracy of the PHQ-9 and PHQ-2 to detect major depressive disorder in primary care. Methods Cross-sectional analyses within a large prospective cohort study (PREDICT-NL). Data was collected in seven large general practices in the centre of the Netherlands. 1338 subjects were recruited in the general practice waiting room, irrespective of their presenting complaint. The diagnostic accuracy (the area under the ROC curve and sensitivities and specificities for various thresholds) was calculated against a diagnosis of major depressive disorder determined with the Composite International Diagnostic Interview (CIDI). Results The PHQ-9 showed a high degree of internal consistency (ICC = 0.88) and test-retest reliability (correlation = 0.94). With respect to construct validity, it showed a clear association with functional status measurements, sick days and number of consultations. The discriminative ability was good for the PHQ-9 (area under the ROC curve = 0.87, 95% CI: 0.84-0.90) and the PHQ-2 (ROC area = 0.83, 95% CI 0.80-0.87). Sensitivities at the recommended thresholds were 0.49 for the PHQ-9 at a score of 10 and 0.28 for a categorical algorithm. Adjustment of the threshold and the algorithm improved sensitivities to 0.82 and 0.84 respectively but the specificity decreased from 0.95 to 0.82 (threshold) and from 0.98 to 0.81 (algorithm). Similar results were found for the PHQ-2: the recommended threshold of 3 had a sensitivity of 0.42 and lowering the threshold resulted in an improved sensitivity of 0.81. Conclusion The PHQ-9 and the PHQ-2 are useful instruments to detect major depressive disorder in primary care, provided a high score is followed by an additional diagnostic work-up. However, often recommended thresholds for the PHQ-9 and the PHQ-2 resulted in many undetected major depressive disorders.